Common withdrawal syndromes and management

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.

6. ALCOHOL WITHDRAWAL

7. 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

8. 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

9. Other pharmacological therapies Barbiturates Oral ethanol Propofol Haloperidol clonidine baclofen

10. 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

11. 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

12. 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.

13. Benzo withdrawal symptoms tremors Anxiety Depression perceptual disturbances dysphoria Psychosis seizures Restlessness Irritablity Insomnia Muscle aches Poor concentration and memory

14. 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

15. Opioids - receptors distributed widely in the: Brain ( supraspinal sites) Spinal cord Digestive tract (peripheral sites)

16. 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)

17. 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

18. MANAGEMENT Methadone Buprenorphine Clonidine Benzodiazepines Antiemetics eg : promethazine Loperamide or octreotide

19. 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