In this discussion, we will go over the complications of alcohol and benzodiazepine (BZD) use disorders, the pharmacologic and harm reduction treatment, and formulate an appropriate treatment plan for patients.
Introduction
Unlike opioid use disorder which is not fatal in most cases, untreated alcohol and BZD disorders can precipitate seizures and death.
When treatment of these disorders, there are two primary stages of treatment: the withdrawal (acute) treatment and the maintenance treatment. It is important to note that there is no medication that treats these disorders, but we can target specific symptoms and therapeutic goals.
Quick definitions. Withdrawal is also referred to as detoxification. It is the immediate effects that are generally the opposite of the medication taken. For example, in BZD withdrawal, we would expect to see agitation, irritability, autonomic dysfunction, and seizure because we use BZD to induce relaxation and treat anxiety. Maintenance is also referred to as prophylaxis or har-reduction treatment. There are three different approaches that can be taken. First is using medications that have a similar mechanism of action as the abused agent. The Second is to use agents that blunt the reward and reinforcement pathways effect. The third is to use agents that make the patients sick when they use the abused agent. This last way is usually the least effective way.
Alcohol Use Disorders
Alcohol is the second most abused substance in the United States. The most abused is caffeine. This may be due to the fact that alcohol has been normalized in the culture and traditions, causing people to don’t conceptualized this as a potential problem.
Alcohol is both a GABA agonist and an NMDA antagonist. So it boosts the inhibition by increasing GABA and stops the activation by decreasing glutamate. Ultimately, it leads to CNS depression. Alcohol has very interesting pharmacokinetics. It doesn’t really have a half-life because it allows a zero-order elimination. This means that alcohol elimination is only dependent on time.
Alcohol dependence prevalence in the U.S. is about 4% of the adult population. And an estimated alcohol dependence caused arrests was 12%.
Remember that it’s DSM-5 that defines alcohol withdrawal criteria. Patients just need to have at least 2 of the withdrawal symptoms that started in the past hours to days after alcohol use cessation.
When evaluating alcohol use disorder, it is important to ask for the exact quantity of alcohol consumption.
The three biggest risk factors for alcohol withdrawal are chronic and heavy drinking, a history of generalized seizures, and a history of delirium tremens.
If the patient has any of these risk factors, they cannot go through ambulatory detoxification protocol and must be admitted inpatient due to the high risk of bad outcomes and seizures.
Timeline of Alcohol Withdrawal Symptoms
- 6-36 hours since last use: GI upset, shaking, tremors, anxiety, autonomic dysfunction (rising blood pressure and sweating)
- 48 hours since last use: Visual, auditory, and/or tactile hallucinations (brain zap), blood pressure continues to rise
- 48-96 hours since last use: Delirium tremens
Please remember that this is the usual timeline, but there will be people who will deviate from this, such as patients with cirrhosis, patients who use a high amount of alcohol, or patients using a high amount of diazepam. The duration of alcohol withdrawal is dependent on how much and how long the patient has been drinking.
Delirium tremens is very bad. It has high rate of mortality associated with it, and it is almost a ticket straight to the ICU. Symptoms of delirium tremens are halluciantions, disorientation, tachycardia, hypertension, fever, agitation, and diaphoresis.
Alcohol Use Disorder is also associated with Wernicke’s Encephalopathy. This is not something that is commonly associated with BZD Use Disorder. This is a type of vitamin B deficiency where patients present with altered mental status, ataxia, and ophthalmoplegia. In the general population, the risk of this is very low because the diet is generally not a problem. This deficiency in thiamine is derived from the fact that alcohol compromises GI absorption, resulting in the GI being unable to absorb any nutrient leading to a deficiency.
Wernicke’s Encephalopathy is typically reversible, but in the case where it is not treated, it can progress to Korsakoff’s Syndrome, which is irreversible. Because of their similar presentation, it is hard to detect Wernicke versus alcohol use disorder. This is why in most cases, it is recommended that the patient is given thiamine parenterally preemptively. It needs to be through the parenteral route because thiamine oral absorption is not very good where only 4.5mg of thiamine is absorbed from a 100 mg tablet in healthy patients.
It is also important to note that magnesium is an important cofactor in thiamine absorption, which is why it’s sometimes supplemented with the thiamine solution.
Benzodiazepine Withdrawal
The pathophysiology is very similar to alcohol use disorder, which is why the management of benzodiazepine is very similar to alcohol use disorder. The duration and onset of the withdrawal are dependent on the type and amount of benzodiazepine the patient was using.
In general, benzodiazepines are used to treat benzodiazepine withdrawal as well. The most common treatment BZDs are lorazepam (rapid onset and short duration), chlordiazepoxide (delayed onset and long duration), and diazepam (very rapid onset and long duration.) Chlordiazepoxide is utilized a lot in ambulatory detoxification due to its reduced risk of abuse and long-acting. The delayed onset of chlordiazepoxide is not a concern due to the less severity of the patient’s presentation.
Alcohol and Benzodiazepine Withdrawal Treatment
Benzodiazepines are the drug of choice when used in combination with the assessment scales (CIWA-Ar for alcohol and BWSQ for BZD.) There are three types of protocols: taper, PRN, and Taper+PRN
Tapers (Fixed-Dose)
Due to the fixed dosing schedule, this option is ideal for institutions where frequent CIWA-Ar cannot be utilized. In general, the dose is reduced by 10-15% per week. This doesn’t mean that CIWA-Ar should not be performed at all. The assessment is still needed to inform us if the treatment is heading in the right direction or not.
PRN (Symptom-Triggered)
This is when treatment benzodiazepine dose is administered based on the assessment scale. The prescription for PRN treatment is below:
Lorazepam 1 mg q 2 hours PRN CIWA-Ar over 8, and lorazepam 2 mg q 2 hours PRN CIWA-Ar over 16
Patients on the PRN protocol tend to use fewer BZDs overall and be on the withdrawal protocol for a shorter period of time.
Taper + PRN
This is where the patient is on a taper protocol with PRN direction for breakthrough symptoms. This is typically used in patients that were drinking large amounts (fifth a day or handle a day) of alcohol daily.
Scenarios That Interfere with CIWA Score
- Patients present with withdrawal from multiple agents (BZD, heroin, and alcohol). In these patients, we would generally want to initiate the alcohol/BZD treatment protocol.
- Patients have a primary psychotic illness with hallucinations (primary axis I diagnosis)
- Patients taking medications that affect heart rate or blood pressure (beta blockers)
- Patients with baseline tremors, such as patients with schizophrenia or traumatic brain injury.
Alcohol Use Disorder (AUD) Maintenance Treatments
There is no maintenance treatment for benzodiazepines because they’re generally not effective.
In the maintenance treatment of AUD, it is important to recognize aggressive comorbidities management along with the maintenance medications is very important.
There are three medications that are used for this: acamprosate, disulfiram, and naltrexone.
Acamprosate
Acamprosate is a GABA agonist and NMDA antagonist (same MoA as alcohol.) Two things that acamprosate is great at are reducing relief cravings and increasing the rate of abstinence.
Acamprosate must be dosed three times daily at 666mg each dose to reduce GI symptoms. Acamprosate is not metabolized by the liver, which makes it a good agent for alcohol use disorder.
There are two types of cravings: reward cravings and relief cravings.
Disulfiram
Disulfiram is no longer routinely used in practice. It inhibits aldehyde dehydrogenase, resulting in acetaldehyde accumulation that leads to the patients becoming very ill. This negative reinforcement does not help with any craving. Additionally, disulfiram can be tough on the liver as well. This medication may be a good option only in patients with a high level of motivation.
Fun note: in some Asian population, they also have problem with aldehyde dehydrogenase being unable to process acetaldehyde, leading to acetaldehyde accumulation. This is why some of their faces get very red (flushing)!
Naltrexone
Naltrexone is an opioid receptor antagonist available in oral and IM formulations. This medication is very effective and can be used as both a preventative measure and a harm-reduction agent. It blunts the “high” associated with reward cravings. A Cochrane review in 2010 found that naltrexone reduced the risk to return to heavy drinking.
Naltrexone is very burdensome on the liver, and the effect can be overwritten by a sufficient level of methadone. The IM formulation does not require an oral trial, which is very nice. The most common side effects are nausea, vomiting, and diarrhea.