Contributor: Dillon Warr, MD
Pharmacist Reviewer: Elizabeth Tencza, PharmD BCCCP
Raise a glass to the GRACE-4 guidelines. These are Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE). The goal of GRACE is to focus on conditions for which there is wide variation in treatment, for which ED-focused clinical practice guidelines do not already exist, and for which patients have frequent ED revisits.
The GRACE initiative has already covered low-risk, recurrent chest pain, low risk, recurrent abdominal pain, and acute dizziness and vertigo. Now, in GRACE-4 they have published guidelines to help guide us on alcohol use disorder, alcohol withdrawal syndrome, and cannabis hyperemesis management in the ED.
In this episode, we review their recommendations and try to offer some practical tips that you can take with you on your next shift.
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Background
-The top 3 forms of substance use disorders worldwide are 1) Alcohol use disorder, 2) opioid use disorder, and 3) cannabis use disorder. Although opioids have garnered much of the attention, alcohol and cannabis affect millions of people and the acute and chronic repercussions of their use frequently land people in the emergency department.
-Although definitive diagnosis of these substance use disorders can require specific DSM-5 Criteria or screening tools, we do not need these labels or make a formal diagnosis to treat these conditions in the emergency department.
-We have guideline recommendations for ambulatory and inpatient management of these conditions. Yet, there are key differences in these practice environments, from possible need for IV medication, to lack of continuity of care with a single physician. Guidance does not specifically exist for ED management.
–The purpose of GRACE-4 is to summarize the available evidence regarding the ED management of these conditions and to provide an evidence-based framework for the evaluation and management of patients in the emergency department.
Guideline Method Overview
- GRACE-4 writing team is a diverse collection of addiction medicine specialists, emergency medicine physicians with advanced training in addiction, GRADE methodologists, and patient representatives with lived experience related to AUD and CHS.
- The use of patient representatives has been a common theme in the GRACE initiative and provides an invaluable perspective.
- Recommendations were based on 3 distinct PICO questions. Each question had extensive literature review and evidence synthesis that dictated their assessment of the quality of the evidence and the strength of their recommends
- PICO 1: In patients 18 years of age or older receiving pharmacologic therapy for moderate to severe alcohol withdrawal in the ED, does the use of adjunctive phenobarbital by any route compared to benzodiazepines alone lead to improvement in outcomes?
PICO 2: In patients 18 years of age or older who present to the ED with AUD who are discharged home, does the prescription of an anti-craving medication, compared to no prescription, improve outcomes?
PICO 3: In patients 18 years of age or older who present to the ED and are suspected to have CHS, does the use of dopamine antag- onists (e.g., haloperidol, droperidol) or capsaicin compared to usual care (or no treatment) lead to improved outcomes? The use of patient representatives has been a common theme in the GRACE initiative and provides an invaluable perspective. - Recommendations were based on 3 distinct PICO questions. Each question had extensive literature review and evidence synthesis that dictated their assessment of the quality of the evidence and the strength of their recommends
Alcohol Withdrawal
-Alcohol withdrawal is a consequence of a hyperexcitable state that results from abrupt cessation of alcohol consumption. Chronic use of alcohol downregulates inhibitory GABA receptors and upregulates excitatory glutamate receptors. When alcohol consumption is abruptly terminated, all this excess glutamate activity sets your brain into a neurotoxic overdrive, leading to autonomic hyperactivity, tremor, insomnia, visual/tactile/auditory hallucinations or illusions, psychomotor agitation, anxiety, seizures, delirium tremens and possibly death. The life threatening nature of alcohol withdrawal makes emergency department management of this condition critical.
-Currently, symptom-dependent treatment with benzodiazepines is the first-line management of this condition. However, phenobarbital is another medication that is increasingly used for the acute management of alcohol withdrawal, particularly in the ICU setting. Mechanistically, phenobarbital could be the better choice–it not only increases GABA signaling through a unique binding site distinct from benzos and alcohol, but unlike benzos, also reduces glutamate receptor activity. There has been some caution in embracing phenobarbital given the potential for serious side effects, such as respiratory depression and hypotension.
Recommendation 1: In adult ED patients (over the age of 18) with moderate to severe alcohol withdrawal who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone (conditional recommendation, FOR) [low to very low certainty of evidence]
-Unfortunately, in their review of the literature, the direct evidence supporting its use in the ED is of mixed quality and highly heterogeneous. Ultimately, 7 articles were included in their analysis: 3 retrospective cohort studies, 2 retrospective chart reviews, and 2 RCTs comparing lorazepam only treatment to phenobarbital only treatment. These articles differed on the severity of AWS, total benzodiazepine dose administered and the phenobarbital dosing strategies. Overall, treatment groups really did not differ on most outcomes. In addition to these ED-based studies, they also reviewed indirect evidence from the ward and the ICU.
-In large contribution from this indirect evidence– the data does suggest small to moderate improvements in several outcomes such a reduction in intubation and mechanical ventilation, reduction in ICU admission rates and length of stay, and reduction in hospital length of stay.
-Of note, GRACE-4 in their review of the literature, did not identify any evidence of increased adverse events such as hypotension or increased intubation with phenobarbital use, although the evidence was of low quality overall.
-Despite the overall low quality and heterogeneous evidence, the GRACE-4 writing group ultimately decided a balance between desirable and undesirable effects probably favors adjunctive phenobarbital over benzodiazepine alone for the treatment of adult ED patients with moderate to severe AWS.
-Sadly, there is not sufficient evidence for them to recommend any specific treatment protocol or algorithm. However, the common theme in several published reports is an institutional protocol with guidance on initial dose, subsequent doses, and monitoring needs.
-They were NOT able to recommend the use of phenobarbital in patients being discharged from the ED based on the existing evidence.
Clinical Management:
Option 1: 130-260 mg IV phenobarbital, with subsequent doses every 15-30 minutes based on clinical need to a max of 15 mg/kg IBW
—Pharmacist Pearl: Onset of phenobarbital is ~5 minutes with a peak in 15-30 minutes. In severe cases, can redose every 15 minutes.
Option 2: 10 mg/kg IV IDEAL Body Weight (MDCalc or EMR) phenobarbital load over 30 minutes followed by 130 mg-260 mg aliquots every 15-30 minutes for persistent symptoms
—Pharmacist Pearl: If you utilize a weight-based dosing regimen, be sure to utilize ideal body weight. This can be calculated using MDCalc or integrated into your EMR order. If a patient is cachectic and their actual body weight is significantly lower than their ideal body weight, can consider lowering their weight-based dose
Pharmacist Perspective:
There are arguments to be made for weight-based dosing strategy and for the fixed-dosing strategy. Liz Tenzca tends to favor the fixed-dosing strategy for several reasons–though with the caveat that it may be institution dependent. 1) Best-practice is for nursing to not compound medications at bedside if it is not an emergency (sterility, diversion risk, dosing errors), and therefore weight-based dosing at many institutions occurs in the pharmacy. This could delay care. Fixed-doses are often more easily stored in the Pyxis and can be rapidly and safely administered. 2) Some patients achieve control at lower doses and doing fixed dosing allows you to stop when you achieve control. Weight-based dosing could lead to over sedation and if the infusion is stopped for whatever reason it can be difficult to tell how much phenobarbital the patient received.
Our pharmacists preferred strategy: 260 mg x 1 and then 130 mg as the subsequent dose until control or until 10 mg/kg. The generally accepted max in 24 hours is 15 mg/kg, though there is not established maximum.
If you are getting to 15 mg/kg of phenobarbital, you should pause and re-evaluate and consider another etiology of their symptoms.
Liver Dysfunction: Phenobarbital is primarily metabolized in the liver. No evidence-based dosing adjustment exists for phenobarbital in cirrhosis or hepatic dysfunction.
Hepatic Encephalopathy is a strong contraindication to phenobarbital given risk of a prolonged comatose state. Be sure the agitation is due to withdrawal and not hepatic encephalopathy.
Benzodiazepines Beforehand?
Paucity of evidence, though preliminary data suggests it is likely safe with no increased mortality.
Conservative management could include use of 130 mg to 260 mg IV phenobarbital aliquots, rather than the 10 mg/kg load.
Take Away 1: Although the evidence is weak, it favors adjunctive phenobarbital over benzodiazepine alone for the treatment of adult ED patients with moderate to severe AWS. Develop an institutional protocol from all clinical stakeholders with guidance on initial dose, subsequent doses, and monitoring needs. Consider the 10 mg/kg IV IDEAL Body Weight phenobarbital load or the 130-260 mg IV phenobarbital aliquots depending on the situation.
Alcohol Use Disorder
-Although formal diagnosis of AUD can be challenging in the emergency department, requiring DSM-5 and probably more time than we have in the ED. However, practically speaking, someone who presents to the ED with consequences or harms of alcohol use meets the minimum requirements for diagnosis.
-Medications for the management of AUD have been available for decades and anti-craving medications (or medication-assisted treatment) have been shown to be effective in reducing the amount of alcohol consumed and heavy drinking days, as well as increasing the # of days abstinent.
-Despite their effectiveness, uptake in prescribing these medications has been low–with only 5.8% of individuals receiving treatment for this disorder, despite 85% of people with AUD engaging with the healthcare system within the previous 12 months.
-Based on the available evidence, the GRACE-4 team wanted to provide guidance on ED management of AUD and offer some possible options for anti-craving medication in the ED.
Recommendation 2: In adult ED patients (over the age of 18) with AUD, we suggest a prescription for an anticraving medication for the management of AUD for patients who desire alcohol cessation (conditional recommendation, FOR) [very low to low certainty of evidence].
Recommendation 2a: In adult ED patients (over the age of 18) with AUD who are not taking opioids, we suggest naltrexone (compared to no prescription) for the management of AUD to prevent return to heavy drinking and/or to reduce heavy drinking (conditional recommendation, FOR) [low certainty of evidence].
Naltrexone: Approved by the FDA for the treatment of both AUD and OUD. It acts as a highly selective opioid antagonist to block endogenous opioids triggered by alcohol and thereby decreases dopaminergic activity, reducing cravings and preventing relapse by reducing the rewarding effects of alcohol. A number of reviews and meta-analyses demonstrate the benefits of naltrexone, with the data showing fewer heavy drinking days and lower risk of relapse.
Good practice statement: A bridging prescription of up to 4 weeks until follow-up with an addiction medicine physician, primary care physician, or other appropriate health care provider can take place is preferred. Monitoring of liver enzymes should be at the discretion of the provider seeing the patient in follow-up. For patients not treated with long-acting benzodiazepines for AWS in the ED, patients should be advised that sudden cessation of alcohol consumption (as a result of anticraving medication) may produce acute AWS. These patients should be counseled to slowly taper consumption and seek treatment for AWS management should symptoms occur.
Recommendation 2b: In adult ED patients (over the age of 18) with AUD, with contraindications to naltrexone, we suggest acamprosate (compared to no prescription) for the management of AUD to prevent return to heavy drinking and/or to reduce heavy drinking (conditional recommendation, FOR) [low certainty of evidence].
–Acamprosate: Another first-line treatment for AUD that is superior to referral to psychosocial support alone, with systematic reviews showing increased probability of abstinence, a significant reduction of heavy drinking days, and reduction in return to use. Mechanism of action is not fully understood.
–Contraindications to naltrexone: severe liver dysfunction (hepatically metabolized), ongoing opioid use (will precipitate withdrawal)
–Good practice statement: A bridging prescription of up to 4 weeks until follow-up where renal function can be monitored with an addiction medicine physician, primary care physician, or other appropriate health care provider is preferred.
–Pharmacist Pearl: Acomprosate is contraindicated for a creatinine clearance <30 and should dose adjust when its <50.
Recommendation 2c: In adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms (conditional recommendation, FOR) [very low certainty of evidence].
-Gabapentin has been studied off-label for AUD; all the evidence is indirect. This recommendation, unlike naltrexone or acamprosate, is more cautious, and reserved for patients with high-self reported withdrawal symptoms when they stop or reduce their alcohol intake or for whom the cost of naltrexone or acamprosate is prohibitive.
–Good practice statement: Given the known misuse potential of gabapentin, a bridging prescription, for example, less than 2 weeks, is preferable to a long-term prescription. Patients should be cautioned about the sedative effects of gabapentin, and it should be prescribed with caution or avoided altogether in patients who use opioids. In patients with high self-reported withdrawal symptoms when they stop or reduce their alcohol intake, consider prescribing gabapentin in addition to naltrexone or acamprosate. Consider a weekly dispensing interval for gabapentin prescriptions longer than 2 weeks.
–Pharmacist Pearl: The dose is higher than you would start someone for neuropathic pain and titrated quicker. Sedation is less of a risk given these patients have fewer GABA receptors from downregulation in the setting of their chronic alcohol use. Doses start at 300 mg TID titrated daily vs the 100 BID-TID slow titration we would use for neuropathic pain.
Take Away 2: People suffering from AUD frequently present to the ED. Someone who presents to the ED with consequences or harms of alcohol use meets the minimum requirements for diagnosis of alcohol use disorder. For those patients interested in pharmacologic therapy that can be seen in follow-up within 4 weeks, prescribing naltrexone or acamprosate, +/- gabapentin, is well within the wheel-house of the emergency medicine physician.
Cannabis Hyperemesis Syndrome
-Cannabis Hyperemesis Syndrome (CHS) is characterized by episodes of frequent and severe vomiting or nausea associated with abdominal pain in patients who regularly and frequently use cannabis. Classically, these patients have improvement in their symptoms with hot showers or baths–though this isn’t required for diagnosis of this condition.
-The legalization of cannabis in many states, its increasing popularity, and the increasing concentrations of THC have led to increased presentations to the ED for this condition.
-Ultimately, the treatment for this condition is cessation of cannabis use. However, symptom control and supportive care must first be rendered in the emergency department. The question then is–what should we do in the emergency department.
-Traditional antiemetics have had low rates of success in treating CHS based on reported cases.
–Good practice statement: IV fluids and nonopioid analgesics could be administered/offered to help with symptoms management.
Recommendation 3a: In adult patients presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management (conditional, FOR) [very low certainty of evidence].
-On their review, there was limited available evidence. However, they found droperidol lowered the median length of hospital stay and length of stay to ED discharge. They found haloperidol resulted in higher treatment success, reduced use of other antiemetics, and had a shorter time to discharge.
-Fears of QTc prolongation have not manifested in follow-up studies with droperidol.
-Anecdotally and in Dr. Warr’s own personal experience, both of these medications work very well for this condition.
Clinical Management
Droperidol Dosing:
-0.625 mg to 2.5 mg of IV Droperidol.
Haloperidol Dosing:
-Lower dosing of Haloperidol recommended based on available evidence (0.05 mg/kg) given higher risk of adverse effects (extrapyramidal symptoms) with no improvement in outcomes at a higher dose.
-2.5 mg of IV Haloperidol is a practical dosing approach for adult patients.
Recommendation 3b: In patients presenting to the ED with CHS we suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management (conditional, FOR) [very low certainty of evidence].
-The evidence supportive of capsaicin in their review was very limited. There was some weak evidence suggesting patients who received capsaicin were less likely to receive rescue analgesics but no difference in length of stay or time to discharge. The recommendation is based mainly on the lack of significant adverse effects, low cost of capsaicin, and the ability for the patient to apply the medication at home after discharge. This may not be on formulary in your ED or may need to come from pharmacy, which could delay care.
–Good practice statement: One member of the SAEM GRACE-4 Writing Team emphasized the importance of recognizing that not all patients experience relief with capsaicin, and clinicians should be prompt in escalating treatment for patients whose symptoms are not alleviated promptly. This member also emphasized that capsaicin should not be used for patients for whom it had not been effective in the past (conditional, FOR) [very low level of evidence].
–Good practice statement: In patients presenting to the ED with CHS, benzodiazepines and opioids should not be used as first-line treatment for CHS symptom management. In balance with the lack of evidence supporting the effectiveness of benzodiazepines and opioids in this setting, and considering prior SAEM GRACE recommendations for avoiding opioids in the management of chronic abdominal pain, opioids should be reserved for patients where pain is the primary concern and in whom haloperidol/droperidol (and if attempted, capsaicin) have not provided prompt relief. we believe the potential risks associated with administration of opioids as initial treatment for CHS outweigh any potential benefit.
–Good practice statement: These interventions should be used in conjunction with anticipatory guidance on the necessity of cannabinoid abstinence for complete symptom resolution. We found no published evidence that reduction in use will prevent CHS; however, anecdotal evidence from our representative with lived experience suggests that in some cases reducing use may reduce frequency of episodes. If the health care team suspects concurrent cannabinoid use disorder based on screening with a validated tool such as the Cannabis Use Disorder Identification Test–Revised (CUDIT-R) consider referral to psychosocial interventions and/ or addiction medicine specialists if available. Hydration and other supportive treatments should not be delayed to administer either haloperidol/droperidol or capsaicin (if the patient would like to try it). Clinicians should educate patients on the rationale for the use of these medications if questioned and caution them about the intensity of burning related to capsaicin application.
–Pharmacy Pearl: The patients should apply it themselves either in the ED or at home.. Make sure you give the patient gloves to apply it. Sinks can be hard to come by for certain patients and you don’t want them getting capsaicin in their eyes and then you have a different complaint to deal with.
Take Away 3: For patients presenting with cannabis hyperemesis syndrome, the use of haloperidol or droperidol is encouraged and is supported by the available, but still limited evidence. Consider capsaicin as an adjunctive therapy given the low risk and cost of this medication. Ultimately, the treatment for CHS is prolonged cessation from cannabis.
References
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Borgundvaag B, Bellolio F, Miles I, et al. Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department. Acad Emerg Med. 2024;31(5):425-455. doi:10.1111/acem.14911 [pubmed]
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