Common withdrawal syndromes and management
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This document summarizes common withdrawal syndromes from alcohol, benzodiazepines, and opioids. It provides an overview of the pharmacology and pathophysiology of withdrawal from each substance and describes the typical signs and symptoms. For alcohol withdrawal, it outlines the stages of withdrawal and recommended pharmacological and non-pharmacological management. For benzodiazepine and opioid withdrawal, it discusses the receptor adaptations that occur with chronic use and contribute to withdrawal symptoms. It also notes recommended treatments which primarily involve tapering the offending agent or using other drugs like clonidine.
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Common withdrawal syndromes and management
- 1. COMMON WITHDRAWAL SYNDROMES AND MX CLAIRE PLINT CME 12/05/2016
- 2. OVERVIEW • ALCOHOL • BENZODIAZEPINES • OPIOID PHARMACOLOGY/PATHOPHYSIOLOGY SIGNS AND SYMPTOMS MANAGEMENT
- 3. 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
- 4. 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.
- 5. 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.
- 7. 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 hrs Generalised tonic clonic seizures Stage IV – after 48 hrs - global confusional state - autonomic hyperactivity - tremors - hallucinations - seizures - hyperadrenergic ALCOHOL WITHDRAWAL
- 9. 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
- 10. 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
- 11. OTHER PHARMACOLOGICAL THERAPIES 1. BARBITURATES 2. ORAL ETHANOL 3. PROPOFOL 4. HALOPERIDOL 5. CLONIDINE 6. BACLOFEN
- 12. 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
- 13. 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
- 14. • 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.
- 15. BENZO WITHDRAWAL SYMPTOMS • TREMORS • ANXIETY • DEPRESSION • PERCEPTUAL DISTURBANCES • DYSPHORIA • PSYCHOSIS • SEIZURES • RESTLESSNESS • IRRITABLITY • INSOMNIA • MUSCLE ACHES • POOR CONCENTRATION AND MEMORY
- 17. 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
- 18. OPIOIDS - RECEPTORS • DISTRIBUTED WIDELY IN THE: • BRAIN (SUPRASPINAL SITES) • SPINAL CORD • DIGESTIVE TRACT (PERIPHERAL SITES)
- 19. Receptor Location Function Mu subtypes Brain: The highest concentration is found in the limbic system. Spinal cord Peripheral sensory neurons GIT Analgesia Physical dependence Respiratory depression Miosis Euphoria Reduced GIT motility Possible vasodilation Kappa subtypes Brain Spinal cord Peripheral sensory neurons Analgesia Convulsant effects Dysphoria Respiratory depression Reduced GIT motility Delta subtypes Brain Peripheral sensory neurons Analgesia, (less than mu)
- 20. 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
- 22. MANAGEMENT • METHADONE • BUPRENORPHINE • CLONIDINE • BENZODIAZEPINES • ANTIEMETICS EG: PROMETHAZINE • LOPERAMIDE OR OCTREOTIDE
- 23. 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
Editor's Notes
- Common problem l - Ethanol withdrawal is common among hospitalized patients, either as a primary reason for admission or as a development during hospitalization for some other illness or injury. - It is a potentially fatal syndrome that occurs after abrupt discontinuation or decrease in consumption of ethanol in individuals who regularly consume ethanol-containing beverages.
- Symptoms of alcohol withdrawal occur because alcohol is a central nervous system depressant. Alcohol - simultaneously enhances inhibitory tone (via modulation of gamma-aminobutyric acid activity) and - inhibits excitatory tone (via modulation of excitatory amino acid activity). Only the constant presence of ethanol preserves homeostasis. Abrupt cessation unmasks the adaptive responses to chronic ethanol use resulting in overactivity of the central nervous system.
- Symptoms are usually present within six hours of the cessation of drinking and may develop while patients still have a significant blood alcohol concentration stage 1 - The first stage occurs 6 to 24 hours or more after the last drink or after a somewhat longer period of markedly decreased ethanol intake. - Manifestations include anxiety, restlessness, decreased attention, tremulousness, insomnia, and craving for alcoholic beverages. stage 2 Stage 2 - Stage 2, which occurs about 24 hours after the onset of abstinence, is characterized by hallucinations, misperceptions, irritability, and vivid dreams. - Hallucinations may be auditory, but more often they are visual or tactile. Formication, the delusional sensation of insects crawling on the skin, and vivid or threatening visual hallucinations are particularly common. - During this stage, the patient may appear otherwise lucid or somewhat confused, hypervigilant, and easily startled or misled. stage 3 Stage 3 - In stage 3, which commonly occurs 7 to 48 hours after cessation of drinking, seizures occur, usually of the grand mal variety. The seizures classically manifest as a cluster of brief, tonic-clonic convulsions, at one time referred to as "rum fits." - A relatively lucid interval, ranging from hours to 2 or 3 days, is sometimes seen between stages 3 and 4. stage 4 Stage 4 - Stage 4 manifests 2 to 6 days, or more, after initiation of abstinence and consists of a global confusional state associated with signs of neuronal excitation and severe autonomic hyperactivity. Tremors, hallucinations, and seizures are common during this stage. Hyperadrenergic manifestations may include diaphoresis, flushing, mydriasis, tachycardia, hypertension, low-grade fever Delirium tremens (DT) is defined by hallucinations, disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis in the setting of acute reduction or abstinence from alcohol. In the absence of complications, symptoms of DT typically persist for up to seven days.
- Patients may be presenting with an element of alcohol withdrawal however we may have to go looking for a differential diagnosis IC bleed Infection Space occupying lesion Trauma Hepatic failure
- Pharmacological therapies (general principles): - The principle underlying pharmacotherapy is the administration of a cross-tolerant agents to achieve light to moderate sedation to ameliorate the severe manifestations of withdrawal (including autonomic and psychomotor hyperactivity), provide subjective relief, protect the patient from self-harm, and allow specific therapeutic interventions until spontaneous recovery occurs
- Down-regulation of neuro-inhibitory GABA receptors in alcohol dependent individual leads to symptoms of GABA deficiency in withdrawal. BZD act at a modulatory site on the the GABAA receptor to facilitate GABA binding to the GABAA receptors, enhance chloride channel opening, and overcome neuroexcitatory symptoms of GABA deficiency
- Barbiturates - The most commonly used agent is phenobarbital. The shorteracting barbiturate pentobarbital also has been employed. (ii) Oral ethanol - has been used but is discouraged, in part because of the risks of aspiration and gastric irritation, and also because their use can be interpreted as reinforcing the acceptability of using alcoholic beverages, either in general or for treatment of withdrawal symptoms. (iii). Propofol - is effective, but it is not a first-line agent and is not recommended unless the airway is secure. (iv) Haloperidol and other neuroleptics: - Haloperidol and other neuroleptic agents are not routinely used because they can lower the threshold for seizures. In selected cases, haloperidol may be used in conjunction with benzodiazepines for marked agitation or hallucinations, but this agent or similar drugs should not be used as monotherapy. 1. Clonidine - may be administered if hyperautonomic symptoms are prominent. - Typical oral dosing is 75-150mcg every 6 to 12 hours. 2. beta-Adrenergic receptor blockers - not recommended for routine use, but, barring contraindications, they may be considered in selected cases as adjunctive agents for controlling severe hyperadrenergic manifestations.
- Small studies More research requires
- exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor.
- Short acting – oxazepam Intermediate acting – lorazepam, temazepam Long acting – diazepam, active metabolites
- Neurons in the LC produce a chemical, noradrenaline (NA), and distribute it to other parts of the brain where it stimulates wakefulness, breathing, blood pressure, and general alertness, among other functions. When opioid molecules link to mu receptors on brain cells in the LC, they suppress the neurons’ release of NA, resulting in drowsiness, slowed respiration, low blood pressure—familiar effects of opioid intoxication. With repeated exposure to opioids, however, the LC neurons adjust by increasing their level of activity. Now, when opioids are present, their suppressive impact is offset by this heightened activity, with the result that roughly normal amounts of NA are released and the patient feels more or less normal. When opioids are not present to suppress the LC brain cells’ enhanced activity, however, the neurons release excessive amounts of NA, triggering jitters, anxiety, muscle cramps, and diarrhea.
- Signs and symptoms of withdrawal may begin 6 to 12 hours after the last dose of a short-acting opioid and 24 to 48 hours after cessation of methadone. Withdrawal symptoms typically peak within 24 to 48 hours of onset, but may persist for several days with short-acting agents and up to two weeks with methadone
- The use of methadone and buprenorphine is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn. Alpha-2 agonists appear to be most effective in suppressing autonomically mediated signs and symptoms of abstinence[46] , but they are less effective for subjective symptoms. Two recent Cochrane reviews compared the efficacy of alpha-2 adrenergic agonists to methadone or buprenorphine for management of withdrawal.[47, 48] Patients experienced decreased side effects and stayed in treatment longer using tapered methadone compared to the alpha-2 agonists clonidine or lofexidine. Buprenorphine was associated with fewer adverse effects than clonidine, and patients were more likely to complete withdrawal with buprenorphine compared with clonidine. Moreover, a second multicenter randomized trial demonstrated that buprenorphine-naloxone was more effective than clonidine for opioid detoxification. Buprenorphine was equally effective as methadone for withdrawal completion, but withdrawal symptoms appeared to resolve more quickly with buprenorphine. In summary, data to date suggest that buprenorphine and methadone are more effective than alpha-2 agonists, such as clonidine, for opioid detoxification, with buprenorphine associated with a shorter duration of withdrawal symptoms. However, all of these medications are effective, and the choice may depend in part on availability. Benzos reduce catecholamine release