Discussion
Although benzodiazepines and phenobarbital are the most common agents used in the treatment of complicated AWS, alternative agents are also effective in the treatment and prevention of complicated alcohol withdrawal and may be considered for use when weighing the risks and benefits of individualized pharmacology.
Clonidine
Activation of the sympathetic nervous system is a key feature of AWS. Previous work has shown that the severity of AWS is positively correlated to the amount of norepinephrine (NE) released in the CNS.49 Inhibition of NE release, as well as other excitatory neurotransmitters, may be accomplished via activation of the alpha-2 adrenergic receptor.50 Additionally, alpha-2 adrenergic receptor agonist (AAG) medications create an anticonvulsant effect via decrease in cyclic GMP within the cerebellum.51 Taken together, AAG effectively decreases excitatory neurotransmission within the CNS, creating an opportunity for treatment of AWS.
The use of clonidine in the management of AWS is supported by seven double-blind randomized controlled trials.49 Subjects treated with clonidine experienced lower mean withdrawal scoring, heart rate, and blood pressure compared with benzodiazepine-treated patients.49 Furthermore, there was less anxiety, better cognitive recovery, and better management of psychological symptoms reported in the clonidine groups.49 Hypotension is the primary adverse effect of clonidine due to its activation of receptor subtypes A and C within the nucleus tractus solitarius.52 As such, consideration should be given to use of other AWS agents in patients with shock or low baseline blood pressures.
Gabapentin
GABA is the principal inhibitory neurotransmitter in the mammalian CNS with target receptors GABAA and GABAB.53 The acute neuroinhibitory effect induced by GABA, primarily on the GABAA receptor, is potentiated by alcohol.54 Over time, neuroadaptation in the presence of chronic alcohol usage leads to a reduction of GABAA receptor populations in the CNS. Although repeated alcohol exposure produces a state of tolerance, abrupt cessation of alcohol may produce clinical consequences consistent with neural disinhibition and excitation.54
Gabapentin’s neuroinhibitory mechanisms of action include increased production of GABA, inhibition of glutamate (an excitatory neurotransmitter) synthesis, and a reduction in NE and dopamine release.49 Gabapentin for the inpatient treatment of AWS is supported by two randomized trials.49 Benefits of gabapentin included reduced anxiety and sedation compared with benzodiazepines, with no serious adverse events. Further advantages of gabapentin are its concomitant analgesic properties and extrahepatic metabolism, creating opportunities for its use in the injured patient population and for those with hepatic dysfunction.55
Intravenous ethanol
The use of intravenous ethanol has been reported in surgical and trauma ICUs to prevent AWS in patients with a history of binge drinking, multiple daily drinks, or a history of AWS. The purported benefits of IV ethanol are effective management of withdrawal symptoms without the excessive respiratory depression and sedation seen with benzodiazepine administration. Through uncontrolled case series, several groups have demonstrated the efficacy and safety of intravenous ethanol and published protocols for its use.15 56 Weinberg et al published a randomized control trial comparing intravenous ethanol to standard benzodiazepine for AWS prophylaxis in a Trauma ICU.14 They found no benefit of intravenous ethanol over diazepam overall, and patients in the intravenous ethanol group had higher rates of agitation. A randomized trial comparing ethanol and lorazepam in a cardiac ICU population showed similar results.57 As intravenous ethanol does not demonstrate improved outcomes over benzodiazepines, intravenous ethanol is not recommended for prophylaxis or treatment of patients with AWS, and the ASAM guidelines do not support the use of IV ethanol for the prevention or treatment of AWS.18
Antiepileptics
Numerous antiepileptic drugs (AEDs), including valproic acid and carbamazepine, have been used and studied as an adjunct or alternative to benzodiazepines. AEDs have a lower potential for abuse and act at targets outside the GABA pathway. A recent systematic review and meta-analysis evaluated 26 randomized controlled trials comparing various AEDs to benzodiazepines or placebo.58 The review found no difference in rate of AWS, seizure, or DTs. There was a non-statistically significant increase in the rate of mild or moderate adverse effects (dizziness, ataxia, nausea, and vomiting) with carbamazepine and valproic acid use. Although the overall quality of evidence was low as analyzed by the cited systematic review and meta-analysis, the use of AEDs is not recommended for prophylaxis or treatment of patients with AWS.58
Dexmedetomidine
Dexmedetomidine has anxiolytic, analgesic, and sedative properties via its actions on brain stem α2A receptors, with onset of action between 10 and 30 min, plasma half-life of 6 min, an elimination ½ life of 2 hours, 70% to 80% and bioavailability.49 Dexmedetomidine acts via a negative feedback mechanism in regulating the release of NE.59 Dexmedetomidine mitigates tachycardia, hypertension, and tremulousness by inhibiting noradrenergic hyperactivity in alcohol withdrawal.59 Dexmedetomidine has shown some efficacy as an adjunct in benzodiazepine refractory DTs, with benzodiazepine and haloperidol sparing effects.60 Although dexmedetomidine is contraindicated in patients with heart block, it has been associated with more bradycardia but less hypotension than propofol.60 There is some support for cognitive preservation during dexmedetomidine infusion.61–63 Of note, dexmedetomidine is not an antiepileptic medication and other agents may be necessary for this indication.64 With the appropriate level of monitoring, it has been used in both intubated and non-intubated patients.
Two small studies demonstrated the efficacy of dexmedetomidine in reducing benzodiazepine requirements. A prospective, double-blind, placebo-controlled trial including 24 severe alcohol withdrawal patients at a single medical ICU found that the addition of dexmedetomidine reduced 24 hour but not 7-day benzodiazepine requirements.65 A single institution, randomized controlled study of 72 ICU patients with AWS found significantly reduced 24 hour diazepam requirements in those receiving adjunctive therapy with dexmedetomidine.66 They also noted improved patient-nurse communication and reduced haloperidol administration in dexmedetomidine patients. A prospective study of 40 AWS patients treated with diazepam or dexmedetomidine infusion demonstrated improved hemodynamics and fewer treatment days in those receiving dexmedetomidine.67 Arguably, dexmedetomidine may warrant additional consideration in geriatric patients as they are at increased risk of respiratory depression with many agents.68 According to the 2020 ASAM Clinical Practice Guidelines, dexmedetomidine is recommended as an adjunct to benzodiazepine treatment, but not as monotherapy, to prevent or treat alcohol withdrawal-related delirium or seizures, and to assist with the control of autonomic hyperactivity and anxiety in inpatients.18
Propofol
Propofol is an agonist for GABAA receptors, resulting in hyperpolarization by increasing the duration of chloride channel opening/conductance by directly activating the chloride ionophore complex.1 49 59–61 69 This activation inhibits firing, thereby inducing sedation and anxiolysis.1 Of note, propofol binds at a different site of the GABAA receptor than benzodiazepines, and, hence, is often used in benzodiazepine refractory cases.60 64 Propofol also reduces glutamate activity, thereby preventing seizures, inhibits NMDA glutamate receptors, and is thought to inhibit other amino acids that may be upregulated in DTs.1 59 60 69 Propofol acts within seconds, duration of action is approximately 10 min, and has a short elimination half-life.61 64 Risks of propofol infusion include hypotension, the rare but potentially fatal propofol-related infusion syndrome, metabolic acidosis, and hypertriglyceridemia.61 Of note, barbiturates and propofol have similar effects on intracranial dynamics and cerebral activity.49 It is not clear if the increased duration of mechanical ventilation and hospital length of stay of patients treated with propofol is secondary to propofol itself or the severity of the withdrawal.60 Two, small, single-center studies demonstrated the efficacy of propofol in alleviating DTs, with one showing no difference in ventilator days, ICU days, or hospital length of stay between patients receiving benzodiazepines versus propofol.69–71 The ASAM guidelines recommend propofol in mechanically ventilated ICU patients with resistant alcohol withdrawal.18 Of note, higher induction doses of propofol are required in patients with AUD, with a recommended IV loading dose of 100 to 200 mg/hour.72