Fran Lowry

December 13, 2012

The prevalence of serotonin syndrome, which, at its most severe, is a potentially life-threatening drug reaction that increases serotonin levels, is strikingly high in patients receiving buprenorphine (Suboxone, Reckitt Benckiser) on an outpatient basis for opioid addiction, a single-center study shows.

Presented here at the American Academy of Addiction Psychiatry (AAP) 23rd Annual Meeting & Symposium, the study showed that 43% of patients attending a single burprenorphine clinic had mild to moderate serontonin syndrome.

Dr. Shawn Cassady

"The Suboxone clinic presented so many cases, so many women having ankle clonus and agitation and tremor, I thought that this was worth reporting. In fact, 43% of our patients showed some degree of serotonin syndrome. Yet, many mild and moderate cases of serotonin syndrome go unrecognized," lead researcher Shawn Cassady, MD, from the First Step clinic, in Cockeysville, Maryland, told Medscape Medical News.

However, he added, the good news is that serotonin syndrome can be easily identified with a simple reflex examination for ankle clonus, involuntary muscular contraction, and relaxation in rapid succession in the ankle.

Serotonin syndrome is primarily seen with selective serotonin reuptake inhibitors (SSRIs). The use of SSRIs has expanded, and many people use them, "which represents a risk factor right there," Dr. Cassady told Medscape Medical News.

"I think that most everyone we see in the clinic is at risk for serotonin syndrome," he added.

SSRIs Only 1 Cause

Early studies indicated that an SSRI overdose was the main cause of serotonin syndrome, but according to Dr. Cassady, this is not the case. "[SSRI overdose] may account for about 15% of serotonin syndrome, but it was only the fatal and severe cases that were recognized. Mild to moderate serotonin syndrome was not."

More recently, serotonin syndrome has also been seen with other medication combinations with hidden or lesser serotonin activity, including buprenorphine.

Dr. Cassady noted that in this study, the prevalence is much higher than previously reported — even higher than rates found in psychiatric clinics.

In this naturalistic study, the investigators examined clinical findings from 58 patients that were recorded from July 2010 to August 2012 during monthly outpatient clinic visits or weekly inpatient treatment for opioid dependence.

All study participants were women who were taking buprenorphine for opioid dependence. They ranged in age from 19 to 69 years (mean, 32.5 years ± 2.8). Of these women, 29 also had bipolar disorder, and 18 had mild traumatic brain injury.

Antidepressants were being used by 28 of the women, and the buprenorphine dose range was 2 to 48 mg/d (mean, 13.5 mg/d ± 2.0). Twenty-three patients had used marijuana, and 21 had a history of benzodiazepine use.

The majority (88%) were white; 4 were African American, 2 Arabic, and 1 Hispanic.

Relapse Risk Factor

The presence of ankle clonus was key to identifying the syndrome, said Dr. Cassady. In this population, it was present in 43%. The severity of ankle clonus was generally mild (3 to 4 beats) or moderate (5 to 7 beats) and lasted from 1 to 4 seconds. Bilateral clonus was seen in 15 patients.

All but 2 patients had tremor in the hands, tongue, or both, which most often presented with an irregular twitchlike component.

Women also showed restless or jumpy legs, but this was not as definite a marker of serotonin syndrome as clonus, Dr. Cassady said. In addition, most women had agitation and anxiety.

Medications thought to contribute to the development of serotonin syndrome were duloxetine, fluoxetine, sertraline, citalopram, escitalopram, buspirone, ziprasidone, amitriptyline, ondansetron, cyclobenzaprine, lithium, oxycodone, dextromethorphan, and high-dose buprenorphine and naloxone.

"It's important to recognize mild or moderate serotonin syndrome, because not recognizing it means that these women will often drop out of treatment and relapse," he said.

Buprenorphine does not appear to play a large role in serotonin syndrome but may increase risk slightly in the presence of other causal agents and medications, he added.

In addition, bipolar disorder, traumatic brain injury, and antidepressant treatment appear to be strongly correlated with the syndrome, although bipolar disorder in and of itself also appears to be an independent risk factor in its development, Dr. Cassady said.

Treatment involves lowering the antidepressant dose or discontinuing the antidepressant altogether. Dr. Cassady said that he also tells patients to avoid taking over-the-counter drugs that contain dextromethorphan and to stop pain medicines, including tramadol, flexeril, and other medications containing serotonin.

"It's important to educate the patients about these other agents so that they can take care of themselves and avoid things that mess them up," Dr. Cassady said.

Clinical "Pearl"

Dr. John Robertson

Commenting on the findings for Medscape Medical News, John B. Robertson, MD, from the Center for Family Psychiatry, Knoxville, Tennessee, said the "pearl" from this study is that clonus is a great way of picking up mild to moderate serotonin syndrome.

"I had not known about that. Oftentimes, you confuse the mild serotonin syndrome with akathisia or other things like anxiety disorders, increased craving, psychosocial stressors, and all these other things that it can be confused with," Dr. Robertson said.

"If you can identify this as a mild serotonin syndrome, then you are going to treat it very differently. Perhaps you will lower the dosages or get rid of some medication, as opposed to adding medication or escalating dosages, so that was the beauty of specifically that finding.

"It's easy for any physician to check somebody's ankle reflex. It doesn't take much expertise, it's readily done. You can also look for the tongue tremor, also a good marker for serotonin syndrome, and then regularity of the hand tremor," he said.

"But the ankle clonus, I thought, was pretty neat. I've not heard about that at all from anybody, so that's pretty important."

Dr. Cassady and Dr. Robertson have disclosed no relevant financial relationships.

American Academy of Addiction Psychiatry (AAAP) 23rd Annual Meeting & Symposium. Abstract poster 34. Presented December 8, 2012.