In emergency departments, psychiatrists are often consulted on patients presenting with agitation. In many cases, these patients are under the influence of substances—either from intoxication or withdrawal. It is important to recognize when a patient is under these effects, as acute management of the agitation will vary drastically depending on which substances have been used. In this article, I’ll share some tips gleaned from my experience in managing these patients, as well as information from the research literature. For more detailed information on emergency psychiatry, I recommend an excellent recent text published by the APA (Riba MB, Ravindranath D, Winder GS, eds. Clinical Manual of Emergency Psychiatry. 2nd rev ed. Arlington, VA: American Psychiatric Association Publishing; 2015).

Evaluation
Whenever a patient presents with agitation, substance misuse is high on my differential diagnosis list. I ask both the patient and collateral contacts about substances, and I order a urine drug screen (UDS), which is cheap, relatively quick, and can change my clinical management. Some patients act offended when asked to provide a sample, but I explain that it’s part of my routine protocol. Know what is included in your hospital’s UDS, as different laboratories will test for slightly different drug metabolites or give you varying degrees of sensitivity and specificity. For example, some tests include buprenorphine while others don’t, and some break down a positive benzodiazepine screen into specific medications (though this usually takes a few days). Serum drug testing can also be done for substances not included on the standard UDS and can give you quantitative data, but this takes longer. In addition to the UDS, I will typically do a brief physical exam focused on signs of substance use, such as elevated vital signs, disordered gait, tremor, slurred speech, and dilated or pinpoint pupils. I also perform a skin examination for sweating, gooseflesh, and track marks.

Alcohol
We’ve all had patients arrive at the emergency department late at night smelling of alcohol. Agitation in these patients can be caused by either alcohol intoxication or alcohol withdrawal. The treatment of most alcohol intoxication is largely supportive, letting a patient “sleep it off.” However, very high alcohol levels can cause decreased body temperature, blood pressure, and respirations while triggering reflex tachycardia, all of which will generally be managed by the emergency department physician. As blood alcohol levels begin to drop, start looking for alcohol withdrawal. In some people with chronic alcohol use disorder, withdrawal can start as soon as 6 hours after the last drink. Someone who came into the emergency department as pleasantly inebriated may wake up combative, yelling, and demanding to leave. You should be familiar with the symptoms of alcohol withdrawal, characterized by sweating, increased blood pressure and heart rate, anxiety, tremors, nausea, and vomiting. In severe cases you may see grand mal seizures, delirium, and hallucinations, which require immediate intervention (Goodson CM, Alcohol Clin Exp Res 2014;38(10):2664–2677). Standard treatment is with a benzodiazepine such as diazepam or lorazepam, or phenobarbital (which can then be tapered). In cases of severe agitation or psychosis not responding to a benzodiazepine, an antipsychotic with low anticholinergic activity such as haloperidol can be used, but it is important to avoid overmedicating and lowering the seizure threshold. And remember that IV hydration combined with IV thiamine (oral thiamine has poor absorption) can prevent Wernicke-Korsakoff syndrome and long-term neurological problems (Latt N and Dore G, Intern Med J 2014;44(9):911–915).

Benzodiazepines
Like alcohol, benzodiazepines act on GABA receptors, and the same general principles apply. However, different benzodiazepines will have different durations of action and half-lives, thus varying the timeline of the intoxication and withdrawal period. Intoxication solely with benzodiazepines is rarely lethal in otherwise healthy adults, but it can cause fatal respiratory depression when combined with opioids, alcohol, or other CNS depressants. Flumazenil is an antidote for benzodiazepines, but it should be given carefully only to those in respiratory depression, as it may shift the patient into immediate withdrawal and seizures. Treatment for benzodiazepine withdrawal is largely the same as for alcohol, but be aware that some longer-acting benzodiazepines like clonazepam can have a withdrawal period of weeks to months and are best tapered over a similar time period.

Opioids
As the opioid epidemic continues, emergency departments have become accustomed to treating opioid withdrawal, which causes agitation related to anxiety and general discomfort. Recognize the telltale signs of opioid withdrawal, including large pupils, runny nose, sweating, gooseflesh, yawning, anxiety, nausea, vomiting, diarrhea, and muscle aches. Unlike alcohol or benzodiazepine withdrawal, opioid withdrawal is rarely lethal by itself, but it may be life-threatening in medically compromised individuals. It’s now the standard of care to provide treatment for opioid withdrawal in emergency settings, not only to address the accompanying discomfort but also to create a bridge to addiction treatment. Buprenorphine is an opioid partial agonist that can quickly relieve the effects of withdrawal. Only give buprenorphine to someone already experiencing at least some withdrawal, as its action will cause immediate withdrawal in someone who is still intoxicated. Other medications can be given for mild withdrawal symptoms, including clonidine and other symptom-triggered treatments, such as NSAIDs for muscle aches, loperamide for diarrhea, trazodone for sleep, and hydroxyzine for anxiety. Benzodiazepines can be helpful in controlling agitation and anxiety, but they should be used with caution. Remember that patients are at greater risk for overdose directly after tapering off of opioids (Davoli M et al, Addiction 2007;102(12):1954–1959). As such, it’s important to be familiar with the resources available for transition to buprenorphine, methadone, or extended-release naltrexone.

Stimulants
Intoxication with direct CNS stimulants is a common cause of severe agitation in emergency settings. Commonly misused CNS stimulants include cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA or ecstasy), and prescription amphetamines. You can identify intoxication by large pupils, tremors, increased heart rate, blood pressure, respirations, and hyperreflexia. Severe intoxication can cause seizures, paranoid delusions, and hallucinations (typically tactile or visual). There is a risk of heart attack or stroke, especially in people who already have cardiovascular risk factors. Always be aware of other substances the patient may be using, such as the combination of alcohol and cocaine—which produces cocaethylene, a potent and long-acting metabolite that carries more risk of sudden death. First-line treatment for agitation from stimulants is to induce sedation with a benzodiazepine. Even if there is psychosis present, benzodiazepines are still preferred, as antipsychotic medications may lower the seizure threshold and may contribute to cardiac arrhythmias and hyperthermia—though this is still under debate in the emergency medicine literature (Connors NJ et al, Am J Emerg Med 2019;pii:S0735-6757(19)30001–30004). Other medications to avoid include beta-blockers, as there is a theoretical risk of worsening hypertension and cardiovascular problems due to an unopposed alpha-adrenergic response.

PCP
Phencyclidine (PCP or angel dust) use has declined since the 1970s, but you may still see dramatic presentations of PCP intoxication. This synthetic substance is an NMDA receptor antagonist and inhibits the reuptake of dopamine, norepinephrine, and serotonin. It is often not included in standard UDS tests, so diagnosis may depend on your clinical skills. Be on the lookout for psychiatric symptoms of anxiety, paranoia, hallucinations, retrograde amnesia, and disorientation, combined with physical symptoms of hypertension, tachycardia, and horizontal or vertical nystagmus (Dominici P et al, J Med Toxicol 2015;11(3):321–325). The psychosis of a PCP intoxication can closely mimic that seen in an acute episode of schizophrenia. Patients may act on paranoid and bizarre delusions with violent behavior toward themselves or others, made more severe due to the decreased response to pain caused by PCP. However, in other individuals, PCP may cause catatonia or stupor, leading to a comatose state that can be severe enough to require intubation. Medical complications usually come from rhabdomyolysis, seizures, or a prolonged comatose state. Agitation control follows similar guidance to that of CNS stimulants—benzodiazepines are preferred to induce sedation, and antipsychotics are to be used with caution due to lowering of the seizure threshold.

Designer drugs
Similar to PCP, some designer drugs can also lead to acute agitation combined with psychosis. This category includes synthetic cannabinoids such as K2 or spice, as well as synthetic cathinones, commonly referred to as bath salts or incense. There are various other street names for these substances, and they don’t usually show up on a UDS. The clinical presentation can be quite dramatic, with severe agitation, mania, and hallucinations, combined with medical complications of electrolyte disturbances, delirium, hypothermia, seizures, and serotonin syndrome (Klega AE and Keehbauch JT, Am Fam Physician 2018;98(2):85–92). If you suspect that a patient is on one of these designer drugs, use benzodiazepines as first-line treatment for agitation, and again use caution with antipsychotics due to lowering of the seizure threshold (Jerry J et al, Cleve Clin J Med 2012;79(4):258–264).

CATR Verdict: Evaluation of the agitated patient in an emergency setting can be challenging, even more so when the agitation is due to substance use. Physical signs and symptoms, laboratory testing, and a thorough collection of history and collateral information are the keys to correct diagnosis. Tailor the treatment to the specific substance responsible for the intoxication or withdrawal, and regularly monitor for changes in the patient’s presentation.