This short piece in the Well blog describes positive results of a 10-week randomized clinical trial, published in JAMA last week, testing a currently marketed combination of the drugs dextromethorphan and quinidine against placebo for the treatment of agitation and aggression in patients with Alzheimer’s disease. While it manages to provide some insight into the study with its scant 226 words, the story also presents readers with an overly optimistic view of the findings, omits discussion of the high costs of this drug, and never clues readers into the potential conflicts of interest at play. The accompanying editorial in the same edition of JAMA provides a more realistic view of the study and its importance; “… the data from the study by Cummings et al are important, but not overwhelming, and a second independent study with longer duration is needed to confirm the treatment effect.”
This matters because as the population ages, an increasing number of people will inevitably develop dementia, including Alzheimer’s, which is estimated to occur in about 5 million people today (according to the National Institute on Aging). As the dementia progresses, it’s not uncommon for people to develop agitated and even aggressive behaviors towards loved ones and caregivers. Behavioral interventions and changes to the environment don’t always help sufficiently, so drug interventions are sought. Stories about these treatments should provide a balanced and realistic view of study findings, as many patients, families, and caregivers are desperate for something that might help.
Cost is always an important factor that should be considered in a story about a potential new use for an existing prescription drug. This is a glaring drawback of this piece, since the drug, Nuedextra, is already marketed and currently approved for “pseudo-bulbar affect” — an unrelated neuralgic condition. (Pseudo-bulbar affect refers to uncontrollable laughing or crying, even though the person doesn’t necessarily feel the emotions of happiness or sadness) . A look at Costco, considered one of the least expensive places to buy drugs, came up with a price of $2,222 for 180 capsules. At 2 capsules daily, this would last 3 months. Citalopram, also helpful for agitation in randomized trials as the authors noted, is one of those $4 prescriptions available at Costco, Target.
The story makes an attempt to quantify the findings: “Aggression scores declined to 3.8 from 7.1 in the dextromethorphan-quinidine group and to 5.3 from 7.0 in those who took a placebo,” so we’ll give the benefit of the doubt on the rating. But we think the story could have provided a lot more context. Is this a 10-point scale? What does this change represent in terms that would mean something to patients and caregivers? The accompanying editorial provides some of the needed explanation when it notes that “a minimum clinically important difference (MCID) has not been established” for this scale and that “The apparently modest numerical benefit, as evidenced by the approximately 1.5-point between-group difference for the primary outcome measure, is therefore difficult to interpret.” The editorial also notes that there was no improvement in the quality of life measurement during the 10-week trial.
Another concern is the story’s description of benefits from the study’s lead author. He says “Fifty-five percent of the people who were on drugs had a 50 percent reduction in their agitation.” Although this is accurate and the drug’s benefits were significantly different from placebo, the placebo group also improved significantly. The story could have noted that there’s a strong placebo effect happening here that accounts for some of the benefits.
No harms are mentioned, despite the fact that significant side effects occurred during the study, and in more than one or two people — most frequently falls, diarrhea, dizziness, and vomiting. The drug is also well known to have significant side effects on heart rhythm — hence the exclusion of patients with heart rhythm problems — and also to raise the levels of commonly used drugs such as digoxin and some of the SSRI class of anti-depressant/anti-anxiety drugs.
A mere 226 words was not enough to do justice to this study. Given that this is a drug that’s already on the market, a few more pieces of information would really have added value. One thing that should have been noted is that the study was done mostly in outpatients, as opposed to people in nursing homes.
No disease mongering, although the study itself is arguably an attempt to expand the drug’s market from a small number of neurological patients (mostly with amyotrophic lateral sclerosis and multiple sclerosis) with “pseudo-bulbar affect” for which the drug is currently approved, to the much larger market of agitation in Alzheimer’s.
The only source quoted was the lead author. He and most of the other authors are listed as consultants to the company that markets the drug and that funded the study (Avanir). Some of the authors are full-time company employees. The company even supplied a writer to “provide assistance” in writing up the study. The authors clearly have deep financial conflicts here, and it’s well known that sponsor-funded studies come out positive more often than those funded independently. None of this was discussed or disclosed.
It would also have been very easy to use the accompanying editorial to provide more balance and context to the story
Although there are no satisfactory drugs available for Alzheimer’s-related agitation, many patients are treated off label with antipsychotic drugs. In addition, numerous drugs are under study in clinical trials. As was noted in the accompanying editorial (but not the story), “There are several additional candidate treatments for agitation in patients with Alzheimer disease. Along with some smaller studies of carbamazepine, oxycarbazine, and prazosin,15 recent larger RCTs of citalopram16 and stepped analgesia20 have begun to provide a more informative evidence base, with further small RCTs and secondary analyses identifying additional potential candidate therapies. These studies represent new territory for investigation, where it will become increasingly important to prioritize potential treatments in terms of further research and potential clinical use.” We thought the story should have provided some of this context.
The story notes that the drug tested is “already in use for treating certain neurological problems,” and we think most readers can work out from that that the drug is available.
To our knowledge, this is the first study to examine the efficacy of dextromethorphan-quinidine in patients with Alzheimer’s disease. The story notes that “Agitation and aggression are common in Alzheimer’s patients, and there is no known safe and effective treatment.” We think that’s enough to establish novelty.
Although Avanir pharmaceuticals issued a news release for the study, the Times apparently conducted an interview with the lead author, demonstrating original reporting that went beyond the news release.