CAPA 2015 Annual Conference

1

MANAGEMENT OF DRUG AND ALCOHOL WITHDRAWAL

Andrew Lowe, Pharm.D.

CAPA Conference

October 8, 2015

OPIOIDS

CAPA 2015 Annual Conference

2

CAPA 2015 Annual Conference

3

MOA Withdrawal

• On cessation of heroin excessive cAMP production occurs causing withdrawal symptoms

Phases of Opioid Withdrawal

1. Anticipatory withdrawal(3‐4 hrs)

Fear of withdrawalAnxietyDrug seeking

2. Early Withdrawal (8-10 hrs)

Anxiety

Restlessness

Nausea

Nasal stuffiness

Abdominal cramps

Drug seeking

Hypertension

Tachycardia

Yawning

Sweating

Rhinorrhea

Lacrimation

Dilated pupils

3. Fully Developed Withdrawal(1-3 days)

Severe anxiety

Restlessness

Muscle spasm

Elevated BP

Fever/Chills

Drug seeking

Tremor Piloerection

Vomiting

Diarrhea

Tachycardia

4. Protracted Abstinence(up to 6 mos.)

Hypotension

Bradycardia

Insomnia

Loss of appetiteLoss of energyCue induced craving

CAPA 2015 Annual Conference

4

Determinants of Withdrawal Severity

• Triggers  and intensity  of withdrawal

– Amount and regularity of use 

– Rate of withdrawal

– Patient physical & psychological condition and expectation

• Settings and the severity of withdrawal

– Presence of opiates vs absence 

– Treatment setting and environment 

– Physician confidence and attitude 

– Medications for symptom relief and 

general nutrition

Detoxification

• Relieve Symptoms of withdrawal

• Reverse neuro‐adaptation from chronic heroin use

• Reduce degree of physical dependence

• Promote long term treatment leading to life style changes

• Transitional  treatment strategy 

Methods and Medications• Methadone and buprenorphine

– Opioids agonist and partial agonist

– Short and long term

• Clonidine and Lofexidine– Non-opioids; alpha adrenergic

agonists

• Antagonists assisted – Naloxone /Naltrexone

– Rapid and ultra-rapid detoxifications

Detoxification• The most common outcome of detoxification, by whatever means and for however long, is relapse. “Detoxification may be good for a lot of things; staying off drugs is not one of them”

CAPA 2015 Annual Conference

5

Clonidine for Opioid Withdrawal

• ‐2 adrenergic agonist binds to pre‐synaptic autoreceptors on adrenergic neurons– In Locus Coeruleus

– Possibly in A1 and A2 cell groups of the caudal medulla that project to BNST (extended amygdala)

• FDA approved for hypertension– Limiting side effect: hypotension

• Reduces W/D signs and sx:– Significantly better than placebo

– Nearly comparable to slow methadone taper

• Doses: 0.1 mg tid to 0.4 mg tid

• Push dose until withdrawal sx abate or diastolic BP <60

• Use adjunctive benzodiazepines, anti-emetics, anti-diarrheals

Rapid &Ultra Rapid Opioid Withdrawal

• Patient placed under deep sedation or general anesthesia 

• Administer opioid antagonists to provoke W/D

• Manage emergent sx with:– Clonidine/ Lofexidine

– Benzodiazepines

– Antiemetics

– Antidiarrheals

• W/D essentially resolved in 12‐24 hours (ultra rapid) or 2‐3 days (rapid)  with patient ± on full dose of antagonist (naltrexone)

Opioid Substitution or Maintenance  Therapy

• Reduce symptoms & signs of withdrawal

• Reduce or eliminate craving

• Blocks effects of illicit opioids

• Restored normal physiology

• Promote psychosocial rehabilitation and non‐drug life style

Maintenance Medications:• Methadone maintenance

(agonist)

• Naltrexone (antagonist)

• Buprenorphine (partial agonist)– Buprenorphine (Subutex)

– Buprenorphine-naloxone (Suboxone)

CAPA 2015 Annual Conference

6

Methadone: Clinical Properties

Orally active synthetic μ opioid agonist with morphine‐like properties

Action—CNS depressant/ Analgesic  

Quick absorption, slow elimination, long half‐life

Effects last 24 hours; once daily dosing maintains constant blood level 

Prevent withdrawal, reduce craving and use 

Long term treatment normalize physiological function

Facilitates rehabilitation

Pharmacodynamics• Full agonist; receptor affinity lower than Ms

– Main action on mu receptors

• inhibit adenyl cyclase =  cAMP

• potasium channel opening

• calcium channel opening

– also inhibit serotonin reuptake

– also non competitive antagonist NMDA receptor

• No known active metabolites; limited toxicity

– No significant cognitive impairment with chronic use

– No organ toxicity with chronic use

ALCOHOL

CAPA 2015 Annual Conference

7

• Prevalence: 7% of the US population

• 24% of all emergency room visits

• 80,000 alcohol-related deaths each year

• 500,000 episodes of alcohol withdrawal requiring treatment per year

• Estimated cost per year: 223.5 billion dollars

The Impact of Alcohol Abuse

19

Stehman CR. Am J Emerg Med. 2013;31:734-42 .Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.Walker B. J Trauma Acute Care Surg. 2013;74(3):926-31.

A. Cessation of (reduction in) alcohol use that has been heavy and prolonged

B. Two or more of the following that develop w/in several hours of cessation of use:– Autonomic hyperactivity– Increased hand tremor– Insomnia– N/V– Transient visual , tactile, or auditory hallucinations– Psychomotor agitation– Anxiety– Generalized tonic-clonic seizures

Criteria for Alcohol Withdrawal – DSM V

20American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Web. [access date: 1 June 2013]. dsm.psychiatryonline.org

C. Symptoms cause distress or impairment

D. Signs and symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal form another substance.

Criteria for Alcohol Withdrawal – DSM V (continued)

21American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Web. [access date: 1 June 2013]. dsm.psychiatryonline.org

CAPA 2015 Annual Conference

8

Pathophysiology of Alcohol Withdrawal

22

Normal Physiology

23

Vs.

Inhibitory Excitatory

Ca+2

Ca+2

NMDA receptor

Stehman CR. Am J Emerg Med. 2013;31:734-42Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Physiology in the Presence of AlcoholAcute Setting

24

Vs.

Inhibitory Excitatory

Ca+2

Ca+2

NMDA receptor

Stehman CR. Am J Emerg Med. 2013;31:734-42Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

CAPA 2015 Annual Conference

9

Physiology in the Presence of Alcohol Chronic Setting

25

Inhibitory• Decrease in number of GABA receptors

•Decrease in sensitivity of GABA receptors to GABA and EtOH

Excitatory• Increase in number of NMDA receptors

•Increase in NMDA sensitivity to glutamate

Stehman CR. Am J Emerg Med. 2013;31:734-42Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Removal of Alcohol

Glutamate activates highly sensitive NMDA receptors

Little GABA present to act on small number of GABA receptors

Agitation

Pathophysiology – Alcohol Withdrawal

26Stehman CR. Am J Emerg Med. 2013;31:734-42

Abnormal vital signs, N/V, 

tremulousness, diaphoresis

Hallucinations, seizures

Delirium tremens

Sign and Symptoms of Withdrawal

27

Time from last drink:

2-6 hours 7-48 hours 48-72 hours

Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

CAPA 2015 Annual Conference

10

• Confusion, delirium, psychosis• Hallucinations• Seizures

• Usually lasts ~5 days

• May be fatal

• Risk factors for development: – Previous Delirium Tremens– Others - unknown

Delirium Tremens

28 Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Treatment of Alcohol Withdrawal

29

• Reduce the severity and duration of symptoms• Reduce mortality• Ease of administration• MOA in EtOH withdrawal:

– Enhance GABA activity increase inhibition

• No clear benefit of one particular agent– Usually choose IV options:

• Diazepam• Midazolam• Lorazepam

Mainstay of Therapy: Benzodiazepines

30Stehman CR. Am J Emerg Med. 2013;31:734-42Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

CAPA 2015 Annual Conference

11

Diazepam Midazolam Lorazepam

Onset of action 1‐5 min 2‐5 min 5‐20 min

Half life 30‐60 hours(30‐100 hours metabolite)

2‐6 hours 9‐21 hours

Active Metabolite?

Yes Yes no

Metabolism Hepatic Hepatic Hepatic

Excretion Renal Renal  Renal/fecal

Dose adjustmentsHepatic/renal impairment Clcr<10 Renal impairment

Specialconsiderations:

Erratic IM absorption, propylene glycol toxicity at 

very large doses

Longer sedation in obese pts and those with low 

albumin

Risks of lactic acidosis and ATN

Choosing a Benzodiazepam: Pros and Cons

31Stehman CR. Am J Emerg Med. 2013;31:734-42Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

1) Load Benzodiazepine:– Diazepam:

• 5-20 mg q 5-10 minutes

– Lorazepam:• 1-4 mg q 10-15 minutes

2) Benzodiazepine doses PRN3) Determine the need for further treatment

May require large doses because of decreased sensitivity of the GABA receptor

Initial Treatment

32Stehman CR. Am J Emerg Med. 2013;31:734-42Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

• Kindling Phenomenon– Episodes of EtOH withdrawal become harder to

treat– Benzodiazepam resistance– Due to permanent alterations in

neurotransmitters/receptors– Consider diagnosis after:

• >40 mg lorazepam• 200 mg diazepam

• Consider other treatment options

Benzodiazepine Resistance

33Stehman CR. Am J Emerg Med. 2013;31:734-42

CAPA 2015 Annual Conference

12

• Propylene Glycol (PG)– Solvent– T1/2 = 1.4-3.3 hrs– Metabolized by liver lactate, acetate, pyruvate– Excreted in urine

• 12-45% unchanged• Clearance decreases as dose increases = saturation

– No established acceptable level of IV PG• PO level max = 25mg/kg/day

– Toxicity profile:• Serum hyperosmolality, lactic acidosis, kidney failure, SIRS

– Diagnosis: osmolar gap at 48hrs• Poor indicators: anion gap and lactic acidosis

– Treatment: Hemodialysis

Propylene glycol toxicity

34Zar T. Seminars in Dialysis. 2007;20(7):217-9.

• Barbiturates– MOA: Directly open Chloride channel in GABA, enhance

GABA binding, increase duration of opening– Promotes benzodiazepine binding to GABA– ADE: respiratory depression, cardiac depression

– Phenobarbital:• 65-260 mg q 15-30 minutes until symptom control• Time to onset: 5-30 minutes• Hepatic metabolism/Renally eliminated• Max: 600mg/24hrs• Very large volume of distribution

Non-Benzodiazepine Options

35Stehman CR. Am J Emerg Med. 2013;31:734-42 Phenobarbital sodium powder for IV injection package insert. Hospira, Lake Forest, IL, 2008.

• Propofol– MOA in EtOH withdrawal: Slowing closure of

Chloride channel in GABA receptor, NMDA antagonist

– Requires mechanical ventillation

– Time to onset= 1-2 minutes

– Dose:• 0-5mg/kg/hr PRN continuous infusion

• 0.25-2 mg/kg intermittent

Non-Benzodiazepine Options

36Stehman CR. Am J Emerg Med. 2013;31:734-42Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

CAPA 2015 Annual Conference

13

• Ketamine– MOA: NMDA receptor antagonist– May be useful in the treatment of EtOH withdrawal

• “Ethanol-like effects”• Does not cause EtOH cravings

– ADE: HTN, tachycardia, pulmonary secretions, respiratory depression, out of body experience

– Initial doses = 0.2-0.5mg/min

– Current Phase 1 clinical trial for the use of Ketamine in the treatment of depression and alcohol dependence

Non-Benzodiazepine Options

37

Krystal JH. Arch Gen Psychiatry. 1998;55:354-60Krystal JH. Ann of NY Acad Sci. 2003;1003:176-184.Dickerson D. J Psychopharm. 2010; 24(2):203-11Harrison YE. Behavor Pharm. 1998;9:31-40.Ketamine for Depression and Alcohol Dependence. Clinical trials.govKetamine Package insert. Bioniche Pharma USA LLC, Lake Forest, IL, 2008.

• Carbamazepine– Limited data– No IV formulation – for mild AWS only

• Antipsychotics– Haloperidol – only use when patient is already adequately

treated• May be beneficial for hallucinations

• Cardiac Medications– Alpha agonists (Dexmedetomidine, clonidine), beta blockers

• Only mask s/s AWS• Use only as adjunct therapy

Adjunct Treatment Options

38Stehman CR. Am J Emerg Med. 2013;31:734-42Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

• Hydration– IV dextrose for hypoglycemia

• Nutritional Supplementation– Thiamine 100 mg x 3 days

– Magnesium

– Folic Acid

• Elevate head of bed to prevent

aspiration

Supportive Care

39Stehman CR. Am J Emerg Med. 2013;31:734-42Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

CAPA 2015 Annual Conference

14

• Role in the body:– Coenzyme for sugar and protein metabolism– Needed for production of GABA and acetylcholine

• Give thiamine before glucose

• Lack of thiamine can cause:– Wernicke’s encephalopathy

• confusion, loss of motor control, abnormal vision

– Korsakoff syndrome• Memory loss, hallucination, confabulation

Thiamine

40

Brust JCM. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Saunders Elsevier; 2007:chap 443.Walker B. J Trauma Acute Care Surg. 2013;74(3):926-31.

• Ethanol is not recommended for treatment of withdrawal:– Variable metabolism – difficult to predict kinetics– Compared to benzodiazepines:

• Shorter duration• Narrow therapeutic window• Lowers the seizure threshold

– Irritates stomach– Damages the liver– Toxic for neutrophils and macrophages– Acetaldehyde accumulation respiratory failure– Prescribing EtOH condones alcoholism

• Is the patient going to drink on discharge?• Lack of controlled studies

Controversial use of EtOH

41 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

• Clinical Institute Withdrawal Assessment Scale for alcohol– Scale 0-7– 10 areas of observation:

• N/V• Tremor• Paroxysmal Sweats• Anxiety, Agitation• Tactile, Auditory, Visual disturbances• HA• Orientation/sensorium

– Interpreting the score:• <9 = Minimal/absent withdrawal• 10-19 = Mild – moderate• >20 = Severe

Monitoring - CIWA

42

CAPA 2015 Annual Conference

15

BENZODIAZEPINES

3 subjective reasons to abuse BENZODIAZEPINES

• Fun/pleasure/buzz/high/rush/sedation

• Numb the mind: seek oblivion, escape so don’t feel part of the world

• Self‐medication: psychiatric issues (anxiety, depression, reduce voices, medication side effects)

• Psychological issues (sleep, relax, improve confidence and low mood, worries and any other distress)

• Drug use (withdrawal, come down and substitution)

Prevention of Benzodiazepine Withdrawal

• No need to give equivalent replacement doses to prevent withdrawal in high dose illicit user (Harrison et al 1984, Williams et al 1996)

• Seizures may occur if high doses stopped abruptly, only if physically dependent

• Long half life prevents most withdrawal, up to 30mg daily to prevent withdrawal fits

• Client complaining of withdrawal usually complaining of lack of high, anxiolytic or sedative effect

• Look for objective evidence of BDZ withdrawal (signs of anxiety and tachycardia, hypersensitivity to light)

CAPA 2015 Annual Conference

16

Benzodiazepine withdrawal

• After Hallstrom 1990• Stop BDZ when pt is emotionally ready to do so: the need for taking them has passed, pt has recovered (returned to premorbid level of functioning), pt is no longer preoccupied with their symptoms, pt and doctor feel time is right, pt learnt about problems and advantages of stopping

• Encourage self‐help, alternative coping skills eganxiety management, cognitive control (CBT not effect during detoxification) 

Dealing with BDZ detox problems

• Continuing anxiety/depression: treat psychiatric problems more effectively

• Difficulty coping with stress: increase psychosocial support

• Difficulty sleeping: reassure and sleep hygiene

• Difficulty coping with BDZ withdrawal symptoms: use longer half‐life BDZ eg diazepam, clonazepam

• Liking benzo too much to reduce it, use slow onset BDZ eg oxazepam

• Using different amounts each day or binging etc, daily pick ups, supervision

How fast to withdraw BDZ?

• Can be very fast if short term use, non dependent, low dose use

• Reductions slower if dependency syndrome and psychological work required (or fits)

• 10mg every 2‐4 weeks if >60mg diazepam, 5mg every 2‐4 weeks if 20‐60mg, 2.5mg every 2‐4 weeks less than 20mg

• Or as tolerated

CAPA 2015 Annual Conference

17

Prolonged withdrawal reaction

• Higgitt et al 1988, 1990, Ashton 1991

• Criteria suggested by Higgett et al (1988)

• ≥3 new complaints on BDZ withdrawal

• ≥2 persist for more than 4 weeks after the last dose

• ≥1 severe enough to interfere with functioning

REVERSAL AGENTS

• Opioids – naloxone

• Benzodiazepines – flumazenil

• Can precipitate withdrawals

• Use only if absolutely needed (i.e., life‐saving measures)

SUMMARY

• Withdrawals can be life‐threatening

• It is important to have a multi‐modal approach

• Avoid reversal agents

• Supportive care

• Social support is crucial