Years ago I treated a university student who presented to the emergency department (ED) after drinking several cans of a popular caffeinated energy drink to “pull an all-nighter” during final exam week. He was tremulous, agitated, and pale, with sinus tachycardia ranging from 140 to 160 bpm and normal blood pressure (BP). The house officer (registrar) working with me that night proposed treating him with a benzodiazepine, but I pointed out he had an important exam to take in a few hours and had driven himself to the ED. Rather than snow him with benzos, I suggested metoprolol, a lipophilic beta-1 blocker with both peripheral and central nervous system effects. Her response to this was, “Oh no, you can’t do that – what about unopposed-alpha stimulation?” It was at this point I realized the level of misinformation regarding this dogma had become so pervasive, that newly-minted physicians were applying it as an absolute contraindication to beta-blocker treatment for all stimulants.
I asked her, “What is unopposed alpha-stimulation?” She replied, “It’s where you give a beta-blocker and their BP immediately skyrockets.” I asked some other house officers nearby: “It’s when they get an arrhythmia after beta-blockers,” and, “They get chest pain and MI right after beta-blockers, but only with cocaine.” “It puts methamphetamine and cocaine patients at high-risk for aortic and coronary artery dissection.” I then asked, “Have you ever seen it or heard of a case?” and there was silence. I was then asked, “Have you?” I told them I had never experienced or heard of a case of this at our hospital in my 20 plus years of emergency medicine, but I had always been looking for it. It was kind of like the emergency medicine equivalent of a snipe hunt.
We gave him IV metoprolol. Within minutes his tachycardia resolved, and he felt back to baseline. We watched him for another hour then discharged him. I called him later that day, and he told me he felt fine, had successfully taken the exam, and learned a good lesson.
“Unopposed alpha-stimulation” – What is it?
The phenomenon of “unopposed alpha-stimulation,” is loosely defined as an acute increase in BP and/or worsening coronary artery vasoconstriction after administration of a beta-blocker. The physiologic mechanisms for this make sense on paper. In the adrenergic system, stimulation of alpha-1 receptors results in smooth muscle contraction and vasoconstriction. Stimulation of beta-1 receptors increases heart rate, conduction, and contractility, whereas stimulation of beta-2 receptors leads to smooth muscle relaxation. A balance between alpha-1 and beta-2 stimulation results in regulation of vascular tone. If a non-selective beta-blocker, such as propranolol, is used that has both beta-1 and beta-2 effects, this balance is disrupted in favor of alpha-1 and vasoconstriction is favored. Another explanation is beta-1 blockade results in decreased heart rate and increased end diastolic pressure and cardiac fiber length, with resultant increase in BP and ventricular contraction from the Frank-Starling Law.
Excessive catecholamine stimulation of the heart results in tachycardia and increased myocardial contractility, which are important determinants of oxygen demand. This eventually results in myocyte injury and infarction from intracellular calcium overload. Beta-blockers have been shown to benefit patients with other medical conditions in which there is excessive endogenous catecholamine stimulation, such as congestive heart failure, thyrotoxicosis, pheochromocytoma, intracranial hemorrhage, trauma, alcohol withdrawal, and more recently, sepsis. These are conditions frequently encountered in the ED. Given the millions of doses of beta-blockers administered each year, why aren’t we hearing about “unopposed alpha-stimulation” for these hyperadrenergic states more often?
I have asked this question to many of my colleagues. Most agree that the dogma is overblown but must accept it because it is so deeply established in the textbooks. At our ED, we have an extraordinary prevalence of methamphetamine-positive patients. During sign-out rounds and in front of a bunch of residents and medical students, a faculty member, who passionately believed in never giving beta-blockers for anything, told me (with a straight face), “It’s because doctors don’t like to report bad events.” Had she experienced it first-hand? “No, but I heard about a case where a meth patient got a beta-blocker and his aorta exploded right after…enough said.” This particular discussion ensued because she had signed out to me a methamphetamine-toxic patient who had been in the ED for 8 hours with a heart rate ranging from 120 to 140 bpm, elevated BP, and rising Troponin I. The patient had received 4 total doses of lorazepam during his ED stay, which was obviously ineffective. As soon as she left the building and the patient was officially my responsibility, I ordered the mixed beta/alpha blocker labetalol, and his tachycardia, hypertension resolved within minutes.
How did this dogma become so entrenched?
It all started in 1985. Ramoska reported the first case of “unopposed alpha-stimulation” in a cocaine-toxic patient who was agitated. After receiving propranolol, the subject’s BP increased from 170/118 to 180/140 mmHg, and heart rate decreased from 112 to 104 bpm. Nothing adverse happened to the patient, and he calmed down and left the ED against medical advice. Then in 1990, Lange published the first prospective investigation of propranolol with cocaine administration, which is considered THE keystone paper by detractors of beta-blocker use for stimulant toxicity. What is interesting is few of these critics have actually dissected and interpreted the details of this study. During cardiac catheterization of volunteers, the investigators injected propranolol directly into the coronary arteries of 10 subjects who received cocaine, which resulted in slightly worsening coronary vasoconstriction and reduced coronary blood flow, despite no change in arterial pressure or rate-pressure product. In half the subjects (four having coronary artery disease) with coronary vasoconstriction following intranasal cocaine administration, propranolol further constricted coronary arteries more than 10%. There was only one adverse event, when a subject experienced complete coronary artery occlusion and ST-elevation that resolved with nitroglycerin. The “unopposed alpha-stimulation” phenomenon and beta-blocker contraindication began to appear in textbooks soon thereafter, and it has remained entrenched to this day based on a study that could or would never be replicated in the ED. Intracardiac propranolol? When was the last time you even used IV propranolol? What about the BP in this study? Why didn’t it rise precipitously in these subjects as in the prior case?
There are only a handful of other cases. In 1991 Sand published a prospective cohort study of seven cocaine-toxic patients treated with esmolol, an ultra-short-acting selective beta-1 blocker. Esmolol decreased heart rate but had an inconsistent effect on BP. There was one treatment failure with esmolol for control of hypertension for which nifedipine was then successfully used. There were also three adverse events in this same study. In one patient, esmolol caused a 15% rise in systolic BP and 50% rise in diastolic, which was then successfully treated with labetalol (“Hey, wait a minute…rescue using another beta-blocker?”). Esmolol caused hypotension in another patient that required reversal with the alpha-agonist phenylephrine (“Huh? I thought there was supposed to be unopposed alpha going on here…”). The third patient had resolution of symptoms of cocaine cardiovascular toxicity with esmolol but subsequently developed vomiting and lethargy requiring intubation. The take-home point from this study is how unpredictable these effects were, even when using a beta-1 selective agent. Was it possible that these unpredictable effects were from the cocaine itself?
Things were quiet after that for many years. Keep in mind this was the era of early beta-blocker treatment of chest pain. We were giving every patient with angina and tachycardia three serial doses of IV metoprolol as soon as they arrived in the ED. A high percentage of these chest pain patients were indulging in white powdered substances and not telling us. Urine tox screens take a while to come back. By all accounts, “unopposed alpha-stimulation” should have been epidemic in proportion. Then in 2007, Fareed published a case report describing a patient with cocaine-induced acute coronary syndrome whose chest pain resolved with nitroglycerin, but tachycardia (115/min) persisted despite diazepam treatment. Two doses of IV metoprolol were given. Ten minutes later the patient developed chest pain, became unresponsive with systolic BP 50 mmHg and heart rate 120 bpm, and expired. Questions from this case include, “Why did the BP not rise immediately after metoprolol,” and “Why did the patient code 10 minutes after metoprolol?” One would assume if “unopposed alpha-stimulation” was to blame, it would have happened directly after the drug was given. Could it have been from the cocaine itself causing acute vasoconstriction unrelated to the metoprolol?
One last case report in 2009 completes the entire body of evidence for this dogma. Izquierdo Gómez reported a patient with ST-elevation acute coronary syndrome who developed ventricular fibrillation. He was successfully treated with electrical defibrillation, after which IV propranolol was administered for diaphoresis, tachycardia, and hypertension. Following this, the patient suffered another episode of chest pain with higher elevation of the inferior ST segments and new reciprocal anterior ST-depression. Urgent coronary angiography demonstrated a moderate stenosis (60%) in the mid-left circumflex artery, and he was later discharged. So there you have it – seven cases total in over 30 years.
So what does all the evidence show?
For the past 3 decades, this contraindication has persisted despite many who have questioned it, such as Freeman, Leikin, Page, Finkel, Mariani, and Schurr. I decided to do a comprehensive systematic review of the topic, which had surprisingly never been done before. I asked the authors of the previous “unopposed alpha-stimulation” studies and reports to join me, as well as some of the most vocal critics of beta-blockers for stimulant toxicity. Ramoska and Lange, plus several other prominent toxicologists, cardiologists, and emergency physicians signed on. None of the critics agreed to join for various reasons. We published two systematic reviews, one for amphetamine and related derivatives, and one for cocaine. It was surprising how many high-quality studies had been done with stimulant-positive subjects who were treated with beta-blockers. For cocaine there were 50 studies and case reports with a total of 1,744 patients, with the 7 aforementioned adverse treatment events.
For amphetamines there were 19 studies and case reports with 227 patients and one possible “unopposed alpha-stimulation” event: Bal reported a 40-year-old male inhaled an unknown powder later tested to be methylamphetamine/ dimethylamphetamine and received IV practolol, a non-specific beta-blocker no longer marketed, for heart rate 150 bpm and BP 200/120 mmHg. His BP later increased to 240/160 mmHg and heart rate dropped to 115 bpm after practolol. There was no bad outcome, and after several hours his vital signs normalized without further treatment. Delayed absorption and metabolism of this unusual batch of amphetamines compounds to active metabolites could have resulted in the noted increase in BP. Interestingly, the authors of this case report felt they should have used labetalol instead for this patient.
So what about mixed beta/alpha blockers like labetalol and carvedilol? Based on the evidence examined in both systematic reviews, there were no cases of bona-fide or even putative “unopposed alpha-stimulation” events. Labetalol was effective at treating concomitant tachycardia and hypertension. If there is concern about “unopposed alpha-stimulation,” then theoretically labetalol should be safe as it has alpha-blocking properties. When I point this out to certain clinicians, invariably the response I get is, “Yeah, but it’s only like a 1-to-9 alpha:beta ratio, so forget it…”
“I don’t care about the evidence, or these patients. My mind is made up…”
One toxicologist, who refused to join the systematic review on cocaine despite my multiple attempts (just short of begging), told me, “I don’t care about this topic. Nobody in the field of Toxicology cares either. My mind is made up. I prefer to study more interesting and important topics, like reversal of direct thrombin inhibitors.” This isn’t the first time I have gotten a similar response. Why should we care about a topic entrenched in textbooks for decades, which can be spouted like mantra from junior physicians and medical students? Why should we care about the health of these drug abusers? After all, they are responsible for their actions and consequences.
Let’s first consider why we should bother treating these patients at all. Many detractors of treating cocaine-intoxicated patient with anything other than benzos justify this by stating, “Cocaine has a short half-life. Just give them benzos, and they will be normal in a couple of hours. Plus the mortality of cocaine-associated chest pain is less than 6%, they’re young, so they are going to do fine no matter what we do. Why take a risk with beta-blockers?” And what if benzos don’t work? “Well then, give them phentolamine.” When was the last time you pushed IV phentolamine on any patient? It’s not even available in our ED. I tried to order it once just to try it out, and the inpatient pharmacist called one hour later to say they had to mix it – could I wait another hour?
Let’s also consider these patients are never going away – the problem of stimulant abuse continues to grow worldwide, with millions of users. This is a big problem. When they get into trouble guess where they are taken? These patients can be a handful when they arrive in the ED – they are often violent, agitated, psychotic, and require a lot of hospital and psychiatric resources. Treating them with rapid, effective, and definitive pharmacological agents is very important, and early treatment can prevent medical complications and unnecessary admissions to the hospital and ICU. They also rarely give a history of pure cocaine or methamphetamine use. What happens if the patient who tells you they used cocaine actually used methamphetamine? The one hour half-life turns into 12 hours, and you suddenly realize why their heart rate and blood pressure never came down using a few aliquots of benzos.
Another issue is cocaine and amphetamine-associated cardiomyopathy, hypertension, and renal failure. We have legions of these patients now in our ED. They are out in the community with ejection fractions of 10-15%, miss dialysis for days, have baseline systolic BP in the 200’s, and still abuse stimulants. They code in the waiting room and in our hospital cafeteria. They are admitted all the time for heart failure tune-ups and emergent dialysis. This is a tremendous cost to society, and a source of significant morbidity to the patient. By not aggressively treating their stimulant-induced chest pain, uncontrolled tachycardia, and hypertension when they are younger, we are indirectly making the problem worse. We also try to help them get drug rehabilitation, but that is a topic for another day.
Stimulants cause excessive catecholamines. Beta-blockers are the only class of medication that directly antagonizes this effect. Based on the results of our systematic reviews we determined alpha-blockers (phentolamine), nitric-oxide mediated vasodilators (nitroglycerin, nitroprusside), and calcium channel blockers treat hypertension, not heart rate. A beta-blocker like labetalol will do both effectively and safely.
Medicine is full of dogmas of the past, and ongoing research helps support, revise, or refute these for the benefit of patients and present-day and future clinicians. When we stop questioning these entrenched beliefs, especially when absolute, we have done a disservice to our patients and ourselves. Chris Nickson of LITFL wrote in a recent email to me regarding this dogma, “I think few things in medicine are absolute,” which is the correct way to think about it. Toxicology is a field that is largely based on case reports of rarely-encountered situations, as it is impossible to do even moderately-sized randomized double-blinded prospective studies of potentially life-threatening conditions. The treatment of cocaine and amphetamine toxicity is a good example. The “unopposed alpha-stimulation” contraindication is based on medical lore and “toxicomythology,” a term coined by toxicologist Richard Dart who wrote, “We must remove entrenched but inaccurate beliefs in the medical literature and challenge new assertions to ensure that they are scientifically valid.”
About John Richards
Professor of Emergency Medicine at the University of California, Davis Medical Center interested in progressive treatment of substance abuse patients in the emergency department. Night shift stimulant expert (espresso).