Article In Brief
Research findings suggest that nabilone, a medication used to manage vomiting and nausea in cancer patients undergoing chemotherapy, may help to lessen non-motor symptoms of Parkinson's disease. Read on to learn more.
Nabilone, a drug used to treat nausea and vomiting in cancer patients undergoing chemotherapy, may help alleviate non-motor symptoms of Parkinson's disease (PD), according to a phase 2 randomized, placebo-controlled study from Austria.
Anxious mood and night-time sleep disturbances were among the symptoms alleviated in PD patients who took nabilone, a synthetic analogue of tetrahydrocannabinol, the psychoactive component of cannabis. There were no serious adverse events during the short study, which was reported online August 5 in Annals of Neurology.
There has been a lot of interest in the Parkinson's community in whether cannabis or related products might relieve both non-motor and motor PD symptoms, and patients often ask their doctors about the potential benefits of using marijuana.
For now, there is little evidence that would support the use of cannabis or cannabinoids in general for motor or non-motor symptoms of PD, and this latest study is not definitive.
“Our trial was a proof-of-concept phase 2 trial,” said Klaus Seppi, MD, professor of neurology and a movement disorders specialist at Innsbruck Medical University in Austria. “Now, a phase 3 trial with nabilone or other cannabinoids would be desirable to confirm the results.”
Non-motor symptoms, including depression, anxiety, cognitive changes, and sleep problems, are common in PD and may precede motor problems. Symptoms often worsen as the disease progresses.
“Non-motor symptoms are a major determinant of quality of life, progressive disability, and dependence in PD patients, but there is a paucity of controlled clinical trial data concerning their treatment,” the study authors wrote.
“The endocannabinoid system plays a significant role in many physiological body functions, although the exact details of the neural circuitry through which it modulates these functions remain uncertain,” they explained.
Nabilone, a synthetic analogue of tetrahydrocannabinol, the psychoactive component of cannabis, “acts as a partial agonist on both cannabinoid 1 and cannabinoid 2 receptors in humans,” the study said in explaining the rationale for testing the drug for non-motor PD symptoms.
The researchers, including lead author Marina Peball, MD, a neurology resident at Innsbruck, conducted the investigation using an enriched enrolled randomized withdrawal design in two phases. First, they enrolled 47 PD patients with stable motor disease and disturbing non-motor symptoms, which was defined as a score of four or more on the Movement Disorder Society-Unified PD-Rating Scale 1 (MDS-UPDRS-1) with two or more points in the item for anxiety or pain. The participants, age 30 or older, underwent open-label nabilone titration, starting with 0.25 mg daily to as much as 2 mg daily, depending on their reported improvement in symptoms and side effects.
Part 2 of the trial included 38 of the original participants who were considered positive “responders” to nabilone. Nine did not advance either because they were non-responders as defined by the study protocol or dropped out, in some cases, due to unwanted side effects.
Thirty-eight patients were randomly assigned to either nabilone at their optimal dose, as established in part or a placebo. This double-blind part of the study lasted four weeks, after which the drugs were tapered.
The primary outcome used to evaluate nabilone versus placebo was the change in the MDS-UPDRS-1 score from the time of randomization to the four-week visit. The MDS-UPDRS-1 is a well-established scale to assess non-motor symptoms in PD.
At the time of randomization, the mean MDS-UPDRS-1 score for the nabilone group was 9.63, and for the placebo group, it was 8.58 (the score is based on a scale of 0-52, with higher scores indicating greater symptom severity). At four weeks, PD patients who had continued taking nabilone had a mean change of MDS-UPDRS-1 score of 1.0 compared with a change of 2.63 in placebo; this meant that those who stopped taking nabilone appeared to have a worsening of their non-motor symptoms compared with when they were taking the drug, with an effect size of 0.66, Dr. Seppi said.
He said the statistical analysis suggested that anxiety and night-time sleep problems may be particularly helped by nabilone. Some patients reported improvements in restless leg syndrome and pain, although the trial was not powered to demonstrate efficacy on different non-motor symptoms, he said.
“It was noteworthy that most PD patients responded to a dose up to 1 mg of nabilone per day, indicating a benefit from even a small dose of cannabinoids,” Dr. Seppi said.
In Part 1, 77 percent of participants experienced adverse events during the open-label titration of nabilone. However, they were mostly mild and transient side effects, including fatigue, postural dizziness, dry mouth, and sleepiness.
Two of the oldest patients reported confusion and delusions during the titration phase; one had to stop taking nabilone, and the other returned to a lower dose, said Dr. Seppi. He advised a “cautious use (of cannabinoids) with elderly patients” and those with orthostatic hypotension.
Limitations of the study included its small size, short duration, and lack of diversity (all-white cohort). Also, the fact that the randomized, double-blind Part 2 component of the trial included only participants who responded well in the open-label phase could have enhanced the positive results of the second phase. The result's generalizability needs to be tested in a larger controlled trial, the study authors said.
Melissa Nirenberg, MD, PhD, FAAN, professor of neurology at the Icahn School of Medicine at Mount Sinai, said she was unable to draw any clinical conclusions from the Phase II study results.
“The study was too small and had too many methodological limitations,” she said. “I don't think you can conclude from this study whether or not nabilone is beneficial for non-motor symptoms of PD.”
She said the study protocol excluded many types of PD patients, including those with impulse control disorders, blood pressure problems, and extreme psychiatric issues. She said the study also did not take into account the various PD medications patients take, such as levodopa, which can influence non-motor symptoms depending on whether a dose of medicine has recently been taken or is wearing off.
Dr. Nirenberg said that because of the way the trial was designed—with part one responders either continuing on nabilone or switching to a placebo—it was impossible to tell the extent to which the difference in non-motor symptoms in the two groups at week four was due to nabilone in those receiving the study drug or negative consequences of nabilone withdrawal in the placebo group.
Alberto J. Espay, MD, MSc, FAAN, professor of neurology at the University of Cincinnati Academic Health Center, said: “The study is interesting, but the results have to be interpreted with caution.”
The enriched enrollment design—randomizing only those who responded to open-label nabilone—“tends to artificially inflate the true effect of an intervention during a trial, at the expense of making the results generalizable to the wider population.”
“The design also limited the ability to look further at those for whom nabilone is futile or might be even harmful. Remarkably, 20 percent of screened patients did not benefit in the open-label phase and were excluded from the phase 2 trial,” said Dr. Espay, director and endowed chair of the James J. and Joan A. Gardner Center for Parkinson's Disease and Movement Disorders.
Dr. Espay also cautioned that the small difference in UPDRS scores between the nabilone and placebo groups at the end of four weeks “was statistically but probably not clinically significant.”
“A larger parallel-design, placebo-controlled randomized clinical trial, without responder enrichment, will be needed to properly inform the role of nabilone in clinical practice,” he said in an email to Neurology Today.
Roseanne Dobkin, PhD, professor of psychiatry at Rutgers University Robert Wood Johnson Medical School, said it is important for PD researchers to explore the potential role of complementary and alternative therapies, especially for non-motor symptoms. She said that while the data on nabilone were promising, “they are in need of replication given some of the unique aspects of this study's design.”
“There is a positive signal there...but more research is needed before the widespread adoption of the therapy,” she said.
Dr. Dobkin, a clinical psychologist and researcher specializing in PD mental health, said non-motor symptoms of PD are often “overlooked and undertreated.”
“At least 70, 80 percent of patients will experience debilitating non-motor symptoms,” such as cognitive changes, depression, insomnia, she said. “For a large proportion of Parkinson's patients, it is the non-motor symptoms that cause more distress.”
She said untreated depression and anxiety, for instance, can lead to more cognitive and motor decline, in turn leading to more caregiving need.
“These non-motor symptoms go hand in hand with the motor symptoms, and when they are not treated optimally, it can put the whole management of Parkinson's into a tailspin.”
She believes that a portion of every clinical visit for a PD patient should focus on non-motor symptoms. She said clinicians need to ask specific questions—not just a general “how are you doing?”—because patients and caregivers may be reluctant to talk about things like depression. She said a question such as “is your mood as good as you'd like it to be?” may yield a revealing response.
Dr. Dobkin said she would like to see the systematic screening for common non-motor symptoms such as depression and anxiety incorporated into every routine PD clinic visit.
Dr. Seppi reported receiving personal fees from AOP Orphan Pharmaceuticals AG that manufactures the drug testing in this study. Dr. Espay has personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, InTrance, Sunovion, Lundbeck, and USWorldMeds. Drs. Nirenberg and Dobkin had no relevant disclosures.