Volume 57, Issue 26 July 14, 2009 CONFRONTING ADDICTION From the 11th Annual Fundamentals of Addiction Medicine, sponsored by the Providence Regional Medical Center, Everett, WA Medically Supervised Withdrawal monitored inpatient detoxification — eg, freestanding detoxifica- tion; 24-hr medical supervision; medically managed intensive John D. Patz, DO, Family Physician, Providence Behav- inpatient detoxification — can occur in high-attention detoxifi- ioral Health Services, Providence Regional Medical Cen- cation unit or in hospital bed ter, Everett, WA Substances and conditions warranting inpatient detoxifica- Success rates of detoxification: study of 100 alcoholics followed for tion: alcohol — history of withdrawal seizures or delirium tre- 8 yr—after detoxification alone, 3% remained sober for 1 yr; after mens (DTs); pregnancy; coexisting medical or psychiatric detoxification and 2 to 3 Alcoholics Anonymous (AA) meetings diagnosis; opioids — consider “grade inflation”; patients now per week, nearly 75% remained sober for 1 yr; study of 100 heroin consume higher quantities of pharmaceutical agents (eg, oxy- addicts followed for 20 yr—after detoxification in hospital bed or codone [eg, OxyContin]); benzodiazepines — patients at risk jail cell, only 3% achieve 1 yr of abstinence; highest success rate for seizure and profound anxiety (71%) at 1 yr in those who went to jail, followed by 1 yr of parole; Laboratory screening: urinalysis for drugs; pregnancy, HIV, alcohol remission rates—success rate at 1 yr with formal treat- hepatitis C, and tuberculosis; check breath or blood alcohol ment after detoxification, 20% (at 3 yr, 25%); when coupled level on admission with AA, success rate at 1 yr nearly 40% (at 3 yr, nearly 50%) Risk for harm: assess suicidal tendencies or feelings of despair; Benzodiazepines: speaker limits prescription of benzodiaze- assess intent to harm others (with duty to inform) pines to recovering patients in clinical practice because they Nutritional support: balanced diet; alcoholism — give thiamine mimic effects of alcohol before calorie supplementation to reduce risk for worsening Opioid dependence: <20% of opioid addicts achieve long-term ab- mentation due to Wernicke-Korsakoff syndrome; give oral fo- stinence; opioid addiction reduces life expectancy by one-third late replacement; opioid addiction — protein calorie malnutri- Changes in brain: drugs of addiction (eg, alcohol, benzodiaze- tion more common pines, cocaine, amphetamines, marijuana, nicotine) cause meso- Nicotine: maintenance drug; triggers mesolimbic dopamine system; limbic dopamine system to release higher amounts of some patients substitute nicotine addiction for alcohol or drugs af- dopamine, resulting in brain changes; changes in dopamine re- ter detoxification; nicotine transdermal patch commonly pre- ceptors and diminished dopamine function reversible; opioids scribed for nicotine replacement; varenicline (Chantix) — in Food and µ receptors — endorphin system extremely complex; devel- and Drug Administration (FDA) trials, 40% stopped smoking; opment of tolerance to opioids demonstrates neuroadaptability FDA trials did not look at patients with mental health conditions; of this system; reversibility of neuroadaptive change unknown patients report vivid dreams and active hallucinations; reasonable American Society of Addiction Medicine (ASAM) dimension to offer smoking cessation during drug or alcohol detoxification; criteria: risk for acute intoxication and/or withdrawal potential speaker recommends against starting bupropion (eg, Wellbutrin) (determine appropriate level of care); coexisting biomedical and Insomnia: associated with opioid withdrawal; trazodone psychiatric conditions; readiness for change; risk for relapse, (Desyrel) — relatively inexpensive; 50 to 100 mg effective in 30% continued use, or ongoing problems; supportive environment to 40% of patients (higher doses may increase efficacy); approved ASAM levels of care: ambulatory detoxification without extended by FDA for depression rather than sleep; quetiapine (Seroquel) — onsite monitoring — eg, physician’s office or home health care atypical antipsychotic; most commonly used to treat manic phase agency; monitored service at predetermined level; ambulatory of bipolar disorder; 25 to 75 mg at bedtime helpful for sleep; ex- detoxification with extended onsite monitoring — eg, day hospi- pensive; other agents — chloral hydrate effective for sleep; tal; clinically managed residential detoxification — eg, social speaker does not prescribe -aminobutyric acid (GABA) receptor detoxification; nonmedical; provides peer support; medically agonists (eg, zolpidem [eg, Ambien], zaleplon [Sonata], and Educational Objectives Faculty Disclosure The goal of this program is to improve management of pa- In adherence to ACCME Standards for Commercial Support, Au- tients undergoing substance withdrawal and to review char- dio-Digest requires all faculty and members of the planning com- acteristics and effects of benzodiazepines. After hearing mittee to disclose relevant financial relationships within the past and assimilating this program, the clinician will be better 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educa- able to: tional activity promotes quality in health care and not a proprie- 1. Recommend appropriate levels of care for detoxifi- tary business or commercial interest. For this program, the cation. following has been disclosed: Dr. Patz is on the Speakers’ Bureau 2. Recognize substances and conditions that warrant for Reckitt Benckiser. Dr. Juergens is on the Speakers’ Bureau for inpatient detoxification. Forest Pharamaceuticals, Lilly, sanofi-aventis, and Wyeth Phar- maceuticals. Dr. Juergens presents information in his lecture that 3. Manage symptoms, such as insomnia and hyperten- is related to off-label or investigative use of a therapy, product, or sion, during alcohol and opioid withdrawal. device. The planning committee reported nothing to disclose. 4. Discuss pharmacokinetic differences of commonly used benzodiazepines. Acknowledgements 5. Describe symptoms of benzodiazepine withdrawal, Drs. Patz and Juergens spoke in Seattle, WA, at the 11th An- and effects of benzodiazepines on cognition and nual Fundamentals of Addiction Medicine Conference, pre- sented March 5-9, 2009, by the Providence Regional Medical psychomotor performance. 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. AUDIO-DIGEST FAMILY PRACTICE 57:26 [Lunesta]; too similar to benzodiazepines; can produce rebound by county-designated mental health professional required insomnia when discontinued); sleep hygiene — advise patients to when patient at risk for harm to self or others arise at same time every day Co-occurring psychiatric disorders: patient history during Management of GI symptoms: reflux — antacids; H2-blockers; substance-free intervals useful; period of sobriety before start- proton pump inhibitors; vomiting — speaker avoids phenothi- ing psychotropic medications recommended; during detoxifi- azines (eg, promethazine [eg, Phenergan], prochlorperazine cation, use of antidepressants without mood stabilizer not [eg, Compazine]) in alcoholics due to potential to lower sei- advisable, as large proportion of patients with bipolar disorder zure threshold; no advantage with ondansetron (Zofran); treat also have substance use disorder; antidepressant alone has diarrhea and constipation 80% chance of causing treatment-induced affective switch, or Neurologic symptoms: primary feature of alcohol withdrawal; mixed state (ie, agitated depression, possibly leading to sui- sweats; tremor; headache; irritability; seizure; DTs; do Clini- cide) in bipolar patients cal Institute Withdrawal Assessment of symptoms to deter- mine need for medication Use, Abuse, and Untoward Effects of Medications for alcohol detoxification: benzodiazepines—in 57 Benzodiazepines studies, effective against seizures, compared to placebo; no Steven M. Juergens, MD, Assistant Clinical Professor of prominent difference between benzodiazepines and other drugs; Psychiatry, University of Washington Medical School, Se- safety data sparse and fragmented; anticonvulsants—data com- paring anticonvulsants to placebo limited; no clear difference attle; Private Practice, Bellevue, WA between anticonvulsants and other drugs; larger, well-defined Introduction: in United States, 1% to 2% use benzodiazepines studies needed on benzodiazepines and anticonvulsants; carba- daily; more commonly used by women than men (3:1), and mazepine (eg, Tegretol) studied most; divalproex (eg, Depakote) more commonly by whites than blacks (2:1); elderly patients commonly used; using benzodiazepines—start with short-act- constitute largest group of long-term users ing agent (eg, lorazepam [eg, Ativan]); move to long-acting Treatment of anxiety and panic disorders: study found mod- agent (eg, chlordiazepoxide [eg, Librium]) and taper slowly; lo- est increase in use of selective serotonin reuptake inhibitors razepam has slightly euphoric effect; early sobriety—feeling of (SSRIs) over 10 yr; benzodiazepines most commonly used restlessness, irritability, and discontent associated with elevated medication for panic disorder; patients using SSRIs did not levels of glutamate; acamprosate (Campral) may be useful in have more favorable outcomes or better rate of remission normalizing glutamate levels than those using benzodiazepines DTs: continue benzodiazepines, and add antipsychotic to con- Benzodiazepine receptor: benzodiazepines enhance synaptic trol symptoms; give haloperidol (eg, Haldol; 2-5 mg q4h) actions of GABA (inhibitory neurotransmitter) and increase with 1 mg of benztropine (eg, Cogentin) to prevent extrapy- frequency of GABA receptor opening (barbiturates and high- ramidal side effects; one-on-one “sitter” helpful (alternative dose alcohol prolong opening of receptor); 1 subunit — 60% to use of restraints); consider lorazepam (not metabolized in of benzodiazepine receptors; associated with sedation, amne- liver) for patients in hepatic failure; in patients with cogni- sia, ataxia, and some anticonvulsant effects; activity site for tive issues, consider head injury and obtain imaging studies zolpidem (eg, Ambien) and zaleplon (Sonata); 2 subunit — Hypertension: due to sympathetic hyperactivity (“fight or 15% of benzodiazepine receptors; associated with anxiolytic flight”); start -blockers low (25-50 mg) and titrate up as effects; activity site for diazepam (eg, Valium), clonazepam needed; be cautious in patients with asthma (atenolol safer (Klonopin), and alprazolam (eg, Xanax; works at 2 and 1 than older -blockers); be cautious in patients on other subunits); benzodiazepines increase affinity of GABA for its “blockers” (eg, calcium channel blockers, 2-blockers); give receptor and augment effects; antagonists used for benzodiaz- oral or IV volume support epine overdose include flumazenil (used to treat cocaine, alco- Opioid detoxification: withdrawal peaks on day 3 or 4; taper se- hol, and amphetamine dependence) dating medications; before returning patients to community, Pharmacokinetics: potency — 0.25 mg of clonazepam equal to hold for additional day with no sedation to ensure withdrawal 5.00 mg of diazepam (1 mg tid of clonazepam equal to 20 mg symptoms do not worsen; before transferring patients to inpa- tid of diazepam); 0.5 mg of alprazolam equal to 5.0 mg of di- tient facility, dose of chlordiazepoxide should be <100 mg, azepam; onset of action — most rapid with diazepam and and phenobarbital <120 mg; since opioids interact with other chlorazepate; half-life and accumulation — alprazolam and biologic systems (eg, endocrine), recovery times vary; metha- lorazepam fairly short acting (in long-term users, onset of done taper primarily done in outpatient federally approved withdrawal symptoms within 1-2 days; 2-3 days in long-term methadone clinics; buprenorphine taper — done as outpa- users of diazepam or clonazepam) tient; determine whether taper should be long or short; with- Metabolism: glucuronide conjugation — half-lives of drugs (eg, drawal symptoms expected at end of taper lorazepam, temazepam [eg, Restoril], oxazepam) remain con- Management of symptoms: hypertension—clonidine; -blockers sistent across ages of patients; metabolism rapid and products (be cautious when using multiple blockers); anxiety—best treat- inactive; microsomal oxidization — half-lives of drugs (eg, di- ment is to talk with patient; hydroxyzine (eg, Vistaril); restless azepam, triazolam [Halcion], midazolam, alprazolam) increase leg syndrome—cyclobenzaprine (eg, Flexeril) of unclear benefit; with age of patient; half-life of diazepam increases from 20 hr low doses of pramipexole (eg, Mirapex) or ropinirole (eg, at 20 yr to 90 hr at 90 yr, and metabolite active, with even lon- Requip); treat insomnia ger half-life; uptake — benzodiazepines highly lipophilic and Buprenorphine vs methadone: no difference in short-term out- rapidly enter brain tissue; rapidity of gastrointestinal (GI) ab- come for detoxification; withdrawal symptoms may resolve sorption rate-limiting step; tablets more rapidly absorbed than more quickly with buprenorphine capsules; most benzodiazepines cross blood-brain barrier; lo- Benzodiazepine detoxification: give longer-acting agent as sed- razepam can be given intramuscularly (IM); uptake of IM diaz- ative (eg, phenobarbital, 30-90 mg q4h); anticonvulsants (eg, epam unpredictable divalproex or gabapentin [eg, Neurontin]) reduce risk for with- Withdrawal symptoms: similar to symptoms of anxiety disorder; drawal seizures and help relieve profound anxiety (continue irritability; anxiety; sweating; headache; muscle ache; insom- for 1 mo after patient leaves detoxification facility); dis- nia; memory difficulties; nausea; depersonalization; delirium; charge to home or inpatient treatment facility with treatment grand mal seizures; difficult to distinguish withdrawal symp- plan; patients with comorbidities may need higher level of toms from symptoms or relapse of original anxiety state; re- care; some patients leave against medical advice; evaluation bound common; causes of increased symptoms — higher doses AUDIO-DIGEST FAMILY PRACTICE 57:26 of benzodiazepines; agents with short half-lives (eg, alpra- Adverse effects of benzodiazepines: memory — impaired consoli- zolam, lorazepam; controversial); longer duration of treatment dation of memory (ie, transfer from short-term to long-term (controversial); rapid taper; agents with higher potency; panic memory); blackouts and antegrade amnesia; elderly most sensi- disorder; refractory symptoms of anxiety and depression; sub- tive to effects; memory improves with discontinuation of drug; stance use; personality disorder; symptoms tend to develop worse with alcohol; psychomotor performance — decreased psy- within 24 hr of stopping short-acting agents, and 3 to 10 days chomotor speed; long-term users may do better than recent start- after stopping longer-acting benzodiazepines; may need to rein- ers; increased likelihood of ataxia and poor balance; decreased stitute benzodiazepine (followed by more gradual taper), or try attention (may impair driving); worse with age, peak levels, in- pregabalin (Lyrica) or gabapentin; usual withdrawal lasts 5 to creased dose, alcohol use; cognition — meta-analysis of 13 stud- 28 days with protracted withdrawal (ie, increased anxiety; grad- ies over 20 yr found long-term users of benzodiazepines ually improves after 1-6 mo) (equivalent of 17 mg diazepam daily average) consistently more Tapering benzodiazepines: 3 yr after successful tapering, 75% impaired than controls across all cognitive categories, including, remain off benzodiazepines (vs 14% who refuse to taper); pa- memory, speed of processing information, verbal memory, motor tients who remained off benzodiazepines for 3 yr had lower lev- control, and general intelligence; after discontinuation of benzo- els of anxiety and depression, compared to patients who diazepines, cognition improved, but never to level of nonbenzodi- continued benzodiazepines; most severe withdrawal associated azepine-using controls (ie, potential for permanent cognitive with quickly eliminated high-potency drugs (eg, alprazolam, lo- defects); falls — increased risk for falls and femur fractures; razepam, triazolam); method — usually takes 2 to 3 mo (can worse with older age, increased dose, recent start of benzodiaze- take years); gradually taper first 50% of dose, and more slowly pine, or use with other agents (eg, other benzodiazepines or anti- over each successive 25%; consider replacement with clonaze- depressants); anxiety and depression —benzodiazepines may pam or barbiturates if patient on short-acting, high potency exacerbate depression; some studies show lower levels of anxiety agent (10 mg of Valium equal to 30 mg of phenobarbital; re- after discontinuation of benzodiazepine; studies show benzodiaz- duce by 30 mg/day); add anticonvulsants (eg, carbamazepine epine users may not be aware of problems with interaction, anxi- [eg, Tegretol], valproic acid); cognitive behavioral therapy and ety, or mood, but family members or friends see problematic group therapy helpful; adding pregabalin (300 mg) effective behavior; be concerned about suicide (often associated with poly- for generalized anxiety disorder drug use; benzodiazepines on board in 35% suicide deaths) Suggested Reading drome Scale (NDSS) and the Wisconsin Inventory of Smoking Amato L et al: Effectiveness of interventions on opiate withdrawal Dependence Motives (WISDM). Nicotine Tob Res 10:1009, 2008; treatment: an overview of systematic reviews. Drug Alcohol Depend Polycarpou A et al: Anticonvulsants for alcohol withdrawal. Co- 73:219, 2004; Barker MJ et al: Cognitive effects of long-term ben- chrane Database Syst Rev 20:CD005064, 2005; Rickels K et al: zodiazepine use: a meta-analysis. CNS Drugs 18:37, 2004; Bruce SE Pharmacologic strategies for discontinuing benzodiazepine treatment. et al: Are benzodiazepines still the medication of choice for patients J Clin Psychopharmacol 19:12S, 1999; Rickels K et al: Psychomotor with panic disorder with or without agoraphobia? Am J Psychiatry performance of long-term benzodiazepine users before, during, and 160:1432, 2003; Gowing L et al: Buprenorphine for the management after benzodiazepine discontinuation. J Clin Psychopharmacol of opioid withdrawal. Cochrane Database Syst Rev 19:CD002025, 19:107, 1999; Smyth B et al: Life expectancy and productivity loss 2006; Lader M et al: Withdrawing benzodiazepines in primary care. among narcotics addicts thirty-three years after index treatment. J Ad- CNS Drugs 23:19, 2009; Ntais C et al: Benzodiazepines for alcohol dict Dis 25:37, 2006; Timko C et al: Long-term outcomes of alcohol withdrawal. Cochrane Database Syst Rev 20:CD005063, 2005; use disorders: comparing untreated individuals with those in alcohol- O'Connor K et al: Cognitive-behavioural, pharmacological and psy- ics anonymous and formal treatment. J Stud Alcohol 61:529, 2000; chosocial predictors of outcome during tapered discontinuation of Vaillant GE: What can long-term follow-up teach us about relapse benzodiazepine. Clin Psychol Psychother 15:1, 2008; O'Connor KP and prevention of relapse in addiction? Br J Addict 83:1147, 1988; et al: Psychological distress and adaptational problems associated Voshaar RC et al: Predictors of long-term benzodiazepine absti- with benzodiazepine withdrawal and outcome: a replication. Addict nence in participants of a randomized controlled benzodiazepine with- Behav 229:583, 2004; Piper ME et al: Assessing dimensions of nico- drawal program. Can J Psychiatry 51:445, 2006. tine dependence: an evaluation of the Nicotine Dependence Syn- Accreditation: The Audio-Digest Foundation is accredited by the Accred- Audio-Digest Foundation is approved as a provider of nurse practitioner con- itation Council for Continuing Medical Education to provide continuing tinuing education by the American Academy of Nurse Practitioners (AANP medical education for physicians. Approved Provider number 030904). 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AAPA accepts AMA Category 1 CME credit for the PRA from orga- Cultural and linguistic resources: In compliance with California Assem- nizations accredited by the ACCME. bly Bill 1195, Audio-Digest Foundation offers selected cultural and linguis- Audio-Digest Family Practice has been reviewed and is acceptable for up to tic resources on its website. Please visit this site: www.audiodigest.org/ 96 Prescribed credits by the American Academy of Family Physicians. CLCresources. AAFP accreditation begins 01/01/09. Term of approval is for one year from Estimated time to complete the educational process: this date. Each issue is approved for 2 Prescribed credits. Credit may be Review Educational Objectives on page 1 5 minutes claimed for 1 year from the date of each issue. Take pretest 10 minutes Audio-Digest Foundation is accredited as a provider of continuing nursing Listen to audio program 60 minutes education by the American Nurses Credentialing Center’s (ANCC’s) Com- Review written summary and suggested readings 35 minutes mission on Accreditation. Audio-Digest designates each activity for 2.0 CE Take posttest 10 minutes contact hours. AUDIO-DIGEST FAMILY PRACTICE 57:26 CONFRONTING ADDICTION To test online, go to www.audiodigest.org and sign in to online services. To submit a test form by mail or fax, complete Pretest section before listening and Posttest section after listening. 1. Before placement for detoxification, a patient is assessed and it is determined that social detoxification with peer support would be of the greatest benefit. Which of the following levels of care described by the American Society of Addiction Medicine would be most appropriate? (A) Ambulatory detoxification without extended onsite monitoring (B) Ambulatory detoxification with extended onsite monitoring (C) Clinically managed residential detoxification (D) Medically monitored inpatient detoxification 2. Inpatient detoxification is warranted in alcoholic patients: (A) With history of withdrawal seizures (C) Who have coexisting bipolar disorder (B) Who are pregnant (D) All the above 3. When prescribed for sleep disturbance associated with opioid withdrawal, _______, a -aminobutyric acid (GABA) receptor agonist, can result in rebound insomnia after discontinuation. (A) Trazodone (Desyrel) (C) Chloral hydrate (B) Quetiapine (Seroquel) (D) Zolpidem (eg, Ambien) 4. Which of the following agents may be particularly useful in patients with feelings of restlessness, irritability, and discontent associated with early sobriety after detoxification? (A) Acamprosate (C) Disulfuram (B) Naltrexone (D) Fluoxetine 5. Which of the following appears to be safest for treatment of hypertension in asthmatic patients undergoing alcohol detoxification? (A) Metoprolol (B) Propranolol (C) Atenolol (D) Nadolol 6. The half-life of which of the following benzodiazepines is increased in older patients, compared to younger patients? (A) Lorazepam (B) Diazepam (C) Temazepam (D) Oxazepam 7. Which of the following is most clearly associated with increased symptoms of benzodiazepine withdrawal? (A) Lower doses of benzodiazepines (C) Benzodiazepines with longer half-lives (B) Rapid taper (D) Benzodiazepines with lower potency 8. When tapering patients off benzodiazepines, adding which of the following should be considered? (A) Carbamezepine or valproic acid (C) Pregabalin (B) Cognitive behavioral therapy (D) All the above 9. Which component of memory do benzodiazepines tend to impair? (A) Acquisition (B) Retention (C) Consolidation (D) Retrieval 10. Which of the following can worsen the effects of benzodiazepines on psychomotor performance? (A) Increased dose (B) Alcohol use (C) Use with other agents (eg, other benzodiazepines or antidepressants) (D) All the above Answers to Audio-Digest Family Practice Volume 57, Issue 24: 1-D, 2-A, 3-B, 4-C, 5-B, 6-A, 7-C, 8-D, 9-C, 10-C 2009 Audio-Digest Foundation • ISSN 0271-1362 • www.audiodigest.org Toll-Free Service Within the U.S. and Canada: 1-800-423-2308 • Service Outside the U.S. and Canada: 1-818-240-7500 Remarks represent viewpoints of the speakers, not necessarily those of the Audio-Digest Foundation.
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