Withdrawal / Including Alcohol Withdrawal

Alcohol Use and Withdrawal

Severity of alcohol use disorder (based on >12 signs, symptoms and lab findings associated with alcohol use disorder): Definition of severity 
  • Mild: 2-3 Sx
  • Moderate: 3-5 Sx
  • Severe : 6 or more Sx
Ref: Uptodate 

Case 39-2012: A 55-Year-Old Man with Alcoholism, Recurrent Seizures, and Agitation NEJM

Recognition and Management of Withdrawal Delirium (Delirium Tremens) NEJM 2014

Electrolyte Changes in the Alcohol Use Disorder 

Lab Changes Can be attributed to the following Physiological Changes

14 % : EtOH dependence 
25 % of admission related to EtOH use 
Telltale signs of chronic alcohol ingestion are precipi- tous decreases in plasma concentrations of phosphate, magnesium, potassium, and calcium in the first 24 to 36 hours after admission 

Endocrine Impact / Neurohormonal Impact
1) Decreased Insulin / Glucagon Ratio
2) Decreased PTH level 
3) Decreased GI absorption of Vitamin D 
4) Increase Cortisol, GH
5) Increased ADH 
6) Increased sympathetic nerve tone - due to intravascular volume depletion

Changes in nutrition / metabolic pathway
1) Increase NADH /NAD ratio - 
- Increase in B-hydroxybutyate : metabolism of alcohol to acetaldehyde and acetate, results in an increased ratio of reduced NADH to oxidized nicotinamide adenine dinucleotide (NAD), which leads to preferential formation of β-hydroxybutyric acid. The consequent increase in the level of β-hydroxybutyrate is important to recognize, since the use of strips or tablets that use a nitroprusside reaction, which is only sensitive to acetoacetate, to detect the presence of ketones may cause the clinician to mistakenly attribute an anion-gap acidosis to some other cause. Direct measurement of β-hydroxybutyrate levels should be performed when alcohol abuse is suspected. 
- The increased ratio of NADH to NAD also favors conversion of pyruvate to lactate, which accounts for increased production of hepatic lactate. Peripheral tissues can oxidize lactic acid, so the degree of lactic acidosis is mild. 
An increased ratio of NADH to NAD leads to an inhibitory effect on hepatic gluconeogenesis that predisposes patients to hypoglycemia, which occurs in approximately one quarter of patients with alcoholic ketoacidosis 
2) Thiamine deficiency 
3) Folate deficiency 

Associated ongoing pathological condition 
1) Diarrhea 
2) Vomiting 
3) Increase Ethanol Level
4) Increased Ventilation 
5) Decreased absorption 
6) Increase Calcium carbonate use due to increase OTC med use 
7) Decrease Solute Intake 

Impact on Kidneys
1) EtOH induced tubular dysfunction in Kidney - The described tubular abnormalities may be related to dysfunction of apically located transporters and to decreased activity of the sodium–potassium ATPase, both of which are related to structural changes in the phospholipid bilayer of the cell membrane. 


2) Mg loss
3) HCO3- loss
4) K loss 
5) Ca loss 

Electrolytes and PH Changes 
1) Low Na
2) Low K 
3) Low Mg
3) PO43- loss - 
Due to : decrease intake (of PO43- rich food, antacid use, vomiting, diarrhea); increased loss (generalized tubular dysfunction, metabolic acidosis related mobilization from bone and pH direct affect in Proximal Tubule; increase PTH, Magnesium deficiency causing direct phosphateuria and functional hypoparathyroidism causing more PO4 reabsorption from bone)
Drop in level after admission or Unmasking is due to : Transcellular shift (with normalization of pH, Increase glycolysis and need of PO43-, such shift exacerbated by Insulin release after glucose administration, respiratory alkalosis, increased catecholamine levels)
Clinical Impact: Muscle Weakness, Rhabdomyolysis, Lactic acidosis, Tissue Ischmia (due to affect on RBC)
4) Decreased Ca++
4) Acidosis (both AG and NAG) : Increase acid - Lactic acid, Ketoacid, small contribution of acetic acid, Bicarbonate loss
Lactic acidosis : 
-Intracellular deficiency of phosphate impairs generation of adenosine triphosphate (ATP) from adenosine diphosphate (ADP). Decreased cellular ATP stimulates phosphofructokinase activity, enhancing glycolysis and lactate production. 
- The increased ratio of NADH to NAD also favors conversion of pyruvate to lactate, which accounts for increased production of hepatic lactate. Peripheral tissues can oxidize lactic acid, so the degree of lactic acidosis is mild.

 5) Alkalosis (both metabolic and respiratory): Loss of HCL during vomitting; Increased Breathing 

Supplement to: Palmer BF, Clegg DJ. Electrolyte disturbances in patients with chronic alcohol-use disorder. N Engl J Med 2017;377:1368-77.

Benzodiazepine Withdrawal
Opiates Abuse / Withdrawal
  • Pathophysiology of Opiate Analgesics / Overdose
    • Receptors: mu, delta, and kappa opioid receptors 
      • Nociceptor receptor location: anterior and ventrolateral thalamus, the amygdala, and the dorsal-root ganglia
      • Brainstem Opiate Receptors: Regulates respiratory response to hypercarbia and hypoxia in co-ordination with dopaminergic neurons
      • Receptors in Edinger-Westphal Nucleus of oculomotor Nerve: control pupilary constriction
      • GI tract: Decrease Gut motility
    • Activated by Endogeneous Peptide, and Exogeneous ligands like Morphine
    • Major clinical features is due to mu receptors
      • Both Dependence, and Analgesic effect
      • Mu receptor desensitization leads to tolerance 
        • BUT these receptor undergo endocytosis causing the resensitization when the mu receptors are expressed back in surface. 
        • Endogeneous Peptide: Absence of tolerance due to endocytosis and resensitization
        • Exogeneous Peptide: Persistent binding leads to desensitization
    • Tolerance to analgesic and respiratory depressive effect
      • Due to mu receptor sensitization (as above)
      • Conditioned Tolerance
      • Note: Respiratory tolerance develops at lower rate slower rate than the analgesic tolerance. This over time put the patient with long history of opiates use at a risk of respiratory failure due to narrow therapeutic window
    • Toxikokinetic of opiates overdose
      • Absorption pattern is often irratic after overdose
      • After absorption, most medications undergo first-order-kinetics i.e constant fraction of drug is converted by enzymatic process per unit of time. However, after overdose, due to saturated biologic process, first pass metabolism switches to zero-order-kinetics from first-order-kinetics.
        • Zero-order-kinetics: 2 Phenomenon adds to severe, delayed onset toxicity.
          • Small increase in the drug dose can lead to disproportionate increase in plasma concentration leading to intoxication
          • Constant amount (NOT fraction)  is metabolized per unit of time. 
  • Look out for 10 clinical features of opiate overdose (Figure 2 of Opiate OD NEJM 2012)
  • Signs of opiate abstinence are: yawning, lacrimation, piloerection, diaphoresis, myalgias, vomiting, and diarrhea 
  • 5 points to avoid pitfalls in management of opiate toxicity
    • 1. Naloxone does not shorten the duration of respiratory depression due to opiates due to its short half life. 
    • 2. Dose of nalaxone required to restore respiration, does not correlate with severity of opiate toxicity. This leads to error in dosing, and in admitting to lower level of care while patient needed higher level of care. 
    • 3. Peak plasma opiate concentration does not correlate with the greatest degree of respiratory depression
    • 4. Early acetaminophen toxicity may go unrecognized
    • 5. Pharmacological response in elderly and children are different than in healthy young adults leading to shortening of the observation period
  • Reference
  • Additional Reading
  • Avoid Opiates in 
    • Fibromyalgia
    • Lower Back Pain
      • Prescribing opiates for > 6weeks in first 6 weeks after acute low back pain, causes increased incidence of patient going into disability 
    • Monitor adherence with
      • Pill count 
      • Drug Test 
    • Should not be driving on initiation or dose titration of any sedatives 

Sedative Drugs:
Hypnotic Drugs:
Nicotine Addition: IN GIM Section