Article In Brief
Injectable rimabotulinumtoxinB reduced sialorrhea in patients with neurologic disorders.
A randomized clinical trial has demonstrated the safety, efficacy, and tolerability of rimabotulinumtoxinB (RIMA) as an adult treatment for sialorrhea, an irksome symptom in many patients with Parkinson's disease or other neurological disorders.
The injectable medication may be preferred for sialorrhea management over currently prescribed oral anticholinergic drugs, the authors of a study published online January 13 in JAMA Neurology suggested.
Both doses administered in the trial were well tolerated and resulted in the reduction of sialorrhea. The onset of therapeutic response was observed at one week after injection, supporting the use of this medication to mitigate sialorrhea in adults.
As many as 74 percent of patients with Parkinson's disease experience an overflow of oral saliva, as do approximately half of patients with amyotrophic lateral sclerosis (ALS), the study authors noted. Sialorrhea also commonly affects stroke survivors.
“We've had great difficulty in treating many of our patients with Parkinson's disease as well as other disorders for sialorrhea, which is a major problem, a common problem, that has significant consequences,” Stuart H. Isaacson, MD, the study's principal investigator and director of the Parkinson's Disease and Movement Disorders Center of Boca Raton, FL, told Neurology Today.
“Over the years, there have been small studies and reports of using botulinum toxin (BoNT) to treat sialorrhea, but there really haven't been significant large studies to demonstrate its efficacy, safety, and tolerability,” said Dr. Isaacson, who is also clinical associate professor of neurology at Florida International University's Herbert Wertheim College of Medicine.
BoNT's possible therapeutic utility in treating sialorrhea initially attracted attention in 2000, when researchers reported administering BoNT type A to nine patients with Parkinson's disease.
When BoNT is injected into the salivary glands, it impedes saliva production by cleaving the SNAP receptor (SNARE) protein complex. This process hinders vesicular docking and decreases acetylcholine's release at the parasympathetic nerve terminals within the salivary gland.
In 2018, the US Food and Drug Administration approved BoNT type A based on the outcomes of a phase 3 study demonstrating efficacy, safety, and tolerability. It is one of seven neurotoxin products, which are antigenically and serologically different but structurally similar.
Like many studies, the current one published in JAMA Neurology, which evaluated BoNT type B, included mainly patients with Parkinson's disease. In addition, this time the researchers also enrolled individuals with ALS, medication (neuroleptic)-induced sialorrhea, adult cerebral palsy, oral cancer, and other suspected causes of excess saliva spillage.
The small sample sizes of each group were inadequate to analyze each disorder separately, but the investigators observed no major differences in the patients with Parkinson's disease compared with those whose sialorrhea was due to other causes.
Study Design, Findings
Investigators conducted a randomized, parallel, double-blind, and placebo-controlled, 13-week clinical trial of RIMA 2500 U and RIMA 3500 U from November 14, 2013 to January 23, 2017. They screened a total of 249 adults with distressing sialorrhea, secondary to any disorder or cause, at 33 sites in the United States, Ukraine, and Russia.
To permit follow-up on an open-label basis, patients had to be capable of participating for one year or longer, or six months for those with ALS. Other inclusion criteria consisted of a minimum unstimulated salivary flow rate (USFR) 20 of 0.2g/min and a minimum Drooling Frequency and Severity Scale (DFSS) score—which range from two to nine—of four.
Patients were excluded if they had previously received an injection of BoNT into the salivary glands. Earlier treatment with a BoNT type A injection at other anatomical sites was permissible if the treatment interval was at least six months and no adverse events were documented.
Patients underwent randomization 1:1:1 to receive RIMA, 2500 U (n=63); RIMA, 3500 U (n=64); or placebo (n=60). Primary outcomes consisted of the USFR change from baseline to week four and the Clinical Global Impression of Change (CGI-C) at week four. The CGI-C scores were documented on a seven-point scale, varying from very much improved to very much worse. Adverse events were recorded throughout the trial.
A total of 176 participated until the study concluded. In comparisons of both doses versus placebo, there were substantial reductions in USFR at week four (p <.001) and improvements in CGI-C scores were statistically significant for both treatment groups (p <.001) at week four. Benefits from treatment were apparent as early as one week after injection and were consistent over the medication cycle spanning about 13 weeks.
Compared with placebo, patients tolerated the RIMA injections well. Self-limited mild to moderate dry mouth, dysphagia, and dental caries were the most frequent adverse events.
The original investigation's strengths stem from its design (randomized, parallel, double-blind, placebo-controlled trial), the large number of subjects (187 patients with 94 percent study completion), evaluation of two doses, and the use of both an objective measure (salivary flow) and a global impression of change, said Kathleen M. Shannon, MD, FAAN, professor and chair of the department of neurology at the University of Wisconsin School of Medicine and Public Health.
“It is not a surprising outcome, since those of us who use rimabotulinumtoxinB to treat sialorrhea in clinical practice know well what an important difference this can make for patients,” Dr. Shannon said.
Most movement disorders specialists have been prescribing this medication to treat sialorrhea associated with neurological disorders. They also may favor it in managing sialorrhea due to other etiologies, she said.
Dr. Shannon has observed limited side effects from the injections. However, dry mouth, which is expected, can be associated with elevated risk of dental caries. The injections may compound swallowing difficulties, but Dr. Shannon said she has not seen this occur in clinical practice.
As to whether this treatment would be better than other options, Dr. Shannon added that “we usually try at least one oral medication for sialorrhea before considering botulinum toxin injection, mainly due to expense and also the need for reinjection every three months, but generally speaking, clinical experience is that botulinum toxin injection is superior to any available medical alternative.”
Anticholinergic medications are rarely used nowadays to treat sialorrhea due to limited efficacy and concerning side effects. For instance, in Parkinson's disease, they can aggravate pre-existing cognitive impairment or introduce new trouble with short-term memory, said Howard Hurtig, MD, professor of neurology emeritus at the Perelman School of Medicine at the University of Pennsylvania.
Dr. Hurtig said he is “a fan” of using either botulinum toxin A or B for management of sialorrhea, citing its direct application. “It's nice that you can inject it into the exact site where the problem lies, in the salivary glands,” he said, calling this “a laser approach instead of a shotgun approach.”
Although the study was funded by industry, the investigators undertook the research and analysis independently, with cooperation from three countries. “Multi-institutional clinical trials, like this one, are a challenge because you have to make sure the study's design is rigorously conceived and that good quality control is uniformly executed in all the places where patients are being recruited,” Dr. Hurtig said.
The high-level evidence is a welcome addition to the field of movement disorders. Most general neurologists are aware of botulinum toxin and typically prescribe it to control spasticity or dystonia, but they may not be familiar with its clinical use for sialorrhea, said Cynthia L. Comella, MD, FAAN, professor emeritus of neurological sciences at Rush University Medical Center in Chicago.
“There's really no other effective method of treating more severe drooling,” Dr. Comella said. “This was a well-executed trial. The study is really quite straightforward,” she said.
Too often, after-market, off-label use has become the norm for helpful interventions such as botulinum toxin, said Dr. Shannon. “This makes it difficult to secure insurance approval for treatments irrespective of their safety and efficacy,” she added, indicating that prior authorization is typically required. “The study's authors are to be congratulated for an excellent study that will doubtlessly lead to better management of neurological disorders.”
Dr. Isaacson was an investigator in the MYSTICOL study and reported receiving consulting fees from US WorldMeds LLC. He also reported receiving honoraria for continuing medical education and has received consulting and promotional speaker fees from Acadia, Acorda Therapeutics, Adamas, Allergan, Amarantus BioScience, Biotie, Britannia, Cynapsus, GE, Global Kinetics Corporation, Impax Laboratories, Ipsen, Kyowa, Lundbeck, Merz Neurosciences, Neurocrine Biosciences, NeuroDerm, Teva Pharmaceutical Industries Ltd., UCB, and US WorldMeds. Dr. Shannon has received research funding from Eli Lilly and Sun Pharma; she is an unpaid consultant for Axial Biotherapeutics and Verge Genomics. Dr. Hurtig had no competing interests.