COMMON WITHDRAWAL SYNDROMES AND MX

CLAIRE PLINTCME 12/05/2016

OVERVIEW

• ALCOHOL• BENZODIAZEPINES• OPIOID

PHARMACOLOGY/PATHOPHYSIOLOGY SIGNS AND SYMPTOMS MANAGEMENT

ALCOHOL

• IN WA IN 2013-2014• 80 PUBLICLY FUNDED ALCOHOL AND

OTHER DRUG TREATMENT AGENCIES PROVIDED:• 20,867 TREATMENT EPISODES• ESTIMATED 15,760 CLIENTS

• ALCOHOL WAS THE MOST COMMON PRINCIPAL DRUG OF CONCERN • 37% OF CLIENTS AND 36% OF

EPISODES

ALCOHOL - PHARMACOLOGY• ACUTE EFFECT

STIMULATION OF GAMMA-AMINOBUTYRIC ACID (GABA) SYSTEM NEUROINHIBITORY

• CHRONIC USE CONFIGURATION CHANGES OF GABA-A RECEPTOR SUBUNITS INDUCES AN INSENSITIVITY TO GABA

MORE INHIBITOR IS REQUIRED TO MAINTAIN A CONSTANT INHIBITORY TONE

AS ALCOHOL TOLERANCE DEVELOPS, THE INDIVIDUAL RETAINS AROUSAL AT ALCOHOL CONCENTRATIONS WHICH WOULD NORMALLY PRODUCE LETHARGY OR EVEN COMA IN RELATIVELY ALCOHOL NAÏVE INDIVIDUALS.

CESSATION OF ALCOHOL OR A REDUCTION FROM CHRONICALLY ELEVATED CONCENTRATIONS RESULTS IN DECREASED INHIBITORY TONE.

EXCITATORY AMINO ACIDS - GLUTAMATE

• BINDS TO THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR, CALCIUM INFLUX LEADS TO NEURONAL EXCITATION.

• ETHANOL INHIBITS GLUTAMATE INDUCED EXCITATION• ADAPTION OCCURS BY INCREASING THE NUMBER OF GLUTAMATE RECEPTORS

IN AN ATTEMPT TO MAINTAIN A NORMAL STATE OF AROUSAL. • CESSATION OF ALCOHOL OR A REDUCTION FROM CHRONICALLY ELEVATED

CONCENTRATIONS RESULTS IN UNREGULATED EXCESS EXCITATION.

Stage I 6-24 hrs- anxiety- restlessness- decreased attention- tremulousness- insomnia- craving

Stage II – 24 hrs- hallucinations (visual, auditory, tactile)- misperceptions- irritability- vivid dreams- confused- hypervigilant

Stage III –

48 hrsGeneralise

d tonic clonic

seizures

Stage IV – after 48 hrs

- global confusional state- autonomic hyperactivity- tremors- hallucinations- seizures- hyperadrenergic

ALCOHOL WITHDRAWAL

NON-PHARMACOLOGICAL MANAGEMENT

• A CALM, NONTHREATENING, PROTECTIVE ENVIRONMENT WITH FREQUENT VERBAL ORIENTATION AND REASSURANCE

• TO RELIEVE ANXIETY AND FEAR AND TO MINIMIZE AGITATION.

• IVH/ELECTROLYTE REPLACEMENT• THIAMINE

PHARMACOLOGICAL THERAPIES• THE AGENT OF CHOICE IS A BENZODIAZEPINE, • GIVEN ORALLY IN MILDER CASES OR I.V. IN MORE SEVERE WITHDRAWAL

STATES. • OPTIONS INCLUDE:

• (I) MIDAZOLAM ADMINISTERED BY INFUSION AND TITRATED TO EFFECT • (II) DIAZEPAM –

• GIVEN INITIALLY IN TITRATED DOSES OF 5 TO 10 MG, AT INTERVALS AS FREQUENT AS EVERY 10 MINUTES IF NECESSARY, UNTIL A CALM BUT AWAKE LEVEL OF CONSCIOUSNESS IS ACHIEVED. - SUBSEQUENT DOSING AT 5 TO 20 MG EVERY 4 TO 6 HOURS IS TYPICALLY REQUIRED

OTHER PHARMACOLOGICAL THERAPIES

1. BARBITURATES2. ORAL ETHANOL3. PROPOFOL4. HALOPERIDOL5. CLONIDINE6. BACLOFEN

BACLOFEN FOR ALCOHOL WITHDRAWAL

• PURE GABA-B RECEPTOR AGONIST• STIMULATORY EFFECTS ARE MAINTAINED IN ALCOHOLICS

• BACLOFEN IN THE TREATMENT OF ALCOHOL WITHDRAWAL SYNDROME: A COMPARATIVE STUDY VS DIAZEPAM. ADDOLORATO ET AL. 2006. • EFFICACY OF BACLOFEN IS COMPARABLE TO THAT OF DIAZEPAM

• TREATING ALCOHOL WITHDRAWAL WITH ORAL BACLOFEN: A RANDOMIZED, DOUBLE BLINDED, PLACEBO CONTROLLED TRIAL. LYON ET AL. 2011• BACLOFEN ASSOCIATED WITH SIGNIFICANT REDUCTION IN USE OF HIGH DOSES OF

BENZODIAZEPINES

BENZODIAZEPINES

• BIND AT THE INTERFACE OF THE ALPHA AND GAMMA SUBUNITS AND, ONCE BOUND, LOCK THE GABA-A RECEPTOR INTO A CONFORMATION THAT INCREASES ITS AFFINITY FOR GABA

• DO NOT ALTER THE SYNTHESIS, RELEASE, OR METABOLISM OF GABA

• POTENTIATE ITS INHIBITORY ACTIONS BY AUGMENTING RECEPTOR BINDING.• INCREASES THE FLOW OF CHLORIDE IONS THROUGH THE GABA

ION CHANNEL, CAUSING POSTSYNAPTIC HYPERPOLARIZATION AND A DECREASED ABILITY TO INITIATE AN ACTION POTENTIAL

• CHRONIC INGESTION OF BZDS LEADS TO CONFORMATIONAL CHANGES IN THE GABA RECEPTOR• ULTIMATELY REDUCE THE RECEPTOR'S AFFINITY FOR THE AGENT AND RESULT IN

DECREASED GABA ACTIVITY

• WHEN BENZOS NO LONGER PRESENT • DECREASED GABA RECEPTOR ACTIVITY HAS LESS INHIBITION OF EXCITATORY

NEUROTRANSMITTERS, AND THUS, THERE IS A PRO-EXCITATORY STATE.

BENZO WITHDRAWAL SYMPTOMS

• TREMORS• ANXIETY• DEPRESSION• PERCEPTUAL DISTURBANCES • DYSPHORIA• PSYCHOSIS• SEIZURES

• RESTLESSNESS• IRRITABLITY• INSOMNIA• MUSCLE ACHES• POOR CONCENTRATION AND

MEMORY

TREATMENT OF BENZODIAZAPINE WITHDRAWAL

• BENZOS, BENZOS, BENZOS….• LONGER ACTING - DIAZEPAM• TAPERED OVER A PERIOD OF A FEW

WEEKS TO MONTHS

BETA BLOCKERS, ANTIPSYCHOTICS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS, AND ANTIHISTAMINES HAVE ALL BEEN SHOWN TO BE INFERIOR TO STANDARD TREATMENT

OPIOIDS - RECEPTORS

• DISTRIBUTED WIDELY IN THE:• BRAIN (SUPRASPINAL SITES)• SPINAL CORD• DIGESTIVE TRACT (PERIPHERAL

SITES)

Receptor Location FunctionMu subtypes Brain: The highest

concentration is found in the limbic system.Spinal cordPeripheral sensory neuronsGIT

AnalgesiaPhysical dependenceRespiratory depressionMiosisEuphoriaReduced GIT motility Possible vasodilation

Kappa subtypes BrainSpinal cordPeripheral sensory neurons

AnalgesiaConvulsant effects DysphoriaRespiratory depressionReduced GIT motility

Delta subtypes BrainPeripheral sensory neurons

Analgesia, (less than mu)

OPIOID WITHDRAWAL

• CHRONIC OPIOID EXPOSURE CAUSES ADAPTATIONS THAT INCREASE EXCITABILITY IN NEURONS IN THE LOCUS CERULEUS (NUCLEUS IN THE PONS)• THE MAJOR NORADRENERGIC CENTRE IN THE BRAIN.

• THE PRESENCE OF OPIOIDS BRINGS THESE NEURONS TOWARD THEIR NORMAL FIRING RATES

• WHEN OPIOIDS ARE NOT PRESENT TO SUPPRESS THE LC ENHANCED ACTIVITY THE NEURONS RELEASE EXCESSIVE AMOUNT OF NA

MANAGEMENT

• METHADONE• BUPRENORPHINE• CLONIDINE• BENZODIAZEPINES• ANTIEMETICS EG: PROMETHAZINE• LOPERAMIDE OR OCTREOTIDE

REFERENCES

• LIFE IN THE FAST LANE• UPTODATE• BACLOFEN IN THE TREATMENT OF ALCOHOL WITHDRAWAL SYNDROME: A

COMPARATIVE STUDY VS DIAZEPAM. ADDOLORATO ET AL. 2006. JOURNAL OF HOSPITAL MEDICINE

• TREATING ALCOHOL WITHDRAWAL WITH ORAL BACLOFEN: A RANDOMIZED, DOUBLE BLINDED, PLACEBO CONTROLLED TRIAL. LYON ET AL. 2011. AMJMED