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Loss of Smell: Current & Emerging Therapies
Julia Casazza • Sep 10, 2023 • 36 hits
While smell loss has devastating effects on patients’ quality of life, many clinicians are unaware of the effective, evidenced-based therapies that can help patients improve their olfactory abilities. Dr. Zara Patel, a Stanford rhinologist and smell disorders expert, recently sat down with BackTable ENT to share her firsthand experience in treating patients with loss of smell. In this article, we review therapies for treatment of smell loss, covering those both currently available, such as smell retraining therapy and nutritional supplements, and those on the horizon like platelet-rich plasma therapy.
This article features excerpts from the BackTable ENT Podcast. We’ve provided the highlight reel in this article, and you can listen to the full podcast below.
The BackTable ENT Brief
• Smell retraining therapy is a highly effective, evidence-based tool to help patients recover olfactory capacity.
• During smell retraining therapy, patients focus on what they should perceive while smelling standardized odors, thus strengthening weakened neural connections important to olfaction.
• The role of nutritional supplementation in treatment of smell loss is extremely limited. Further study is needed to identify nutrients that might stimulate olfactory recovery.
• Evidence exists for high-dose omega-3 in prevention of smell loss amongst patients undergoing endoscopic skull base surgery. Patients on anticoagulation and patients with bleeding disorders cannot take omega-3 supplements, as these supplements have blood-thinning effects.
• Platelet-rich plasma injection appears to be a safe, highly effective therapy for smell loss in patients with post-viral olfactory dysfunction.
Table of Contents
(1) Smell Retraining Therapy: An Underutilized Tool for Loss of Smell
(2) Nutritional Supplements for Smell Loss: Evidence-Based or Purely Aspirational?
(3) Platelet-Rich Plasma (PRP) Therapy: A Novel Intervention with Promising Evidence for Loss of Smell
Smell Retraining Therapy: An Underutilized Tool for Loss of Smell
Smell retraining therapy is an evidence-based therapy that restores smell by “exercising” the olfactory system. In smell retraining therapy, patients are instructed to place an odor from a sample kit under their nose twice a day and think about what the odor should smell like. The four standard odors used in training are rose, lemon, clove, and eucalyptus. Experts chose these as the inital four odors in the kit because they are well-studied and were shown to stimulate different kinds of olfactory receptor neurons. After one to three months of training, patients introduce new odors to their repertoire. Manifesting clinically meaningful improvements in smell requires six months of dedicated training. Parallel use of nasal steroid irrigations can improve smell retraining therapy outcomes by decreasing nasal inflammation.
[Dr. Gopi Shah]
Tell me about smell retraining, how you prescribe it, if you will, meaning are there four standard smells? Many people will show me Amazon's got all these smell retraining sticks and kits, you can get 10, you can get 5. How often do they have to change the smells out? Do they change the smells out? Tell me the instructions that you have. What are your instructions? That's what we want to know. What are Zara Patel's instructions on smell retraining?
[Dr. Zara Patel]
There's a lot of people out there trying to make money on these patients. The first thing that I will tell you is that I ran a randomized control trial, the very first randomized control trial in olfactory training in the United States, proving that it does not matter the brand. It does not matter the concentration of the odorant. It does not matter the purity of the odorant. It just matters if the essential oil has a smell, a smell that the patient will recognize as what that smell is supposed to smell like.
All these fancy kits out there, all these really expensive, like, "Oh, this is organic, and this is the most pure," your patients do not need to be spending all their entire paycheck on olfactory training. It should be pennies on the dollar that it costs them to get these smells in just a very simple essential oil and do this on their own.
The instructions are, yes, we start with four particular odors. They are rose, lemon, eucalyptus, and clove. The reason we start with those four odors is that, number one, they've been studied the most, so we know that those are the ones that can have an impact. Number two, they're in different categories of odorants, so they will be stimulating different types of olfactory receptor neurons inside the epithelium. You don't want people to just train on all fruity or all floral. They'll miss stimulating a lot of those other neurons in there if they do that.
We start with those four. I tell people, you just hold it under your nose. You breathe in and out. You don't have to do a big sniff, and what you should do, what's the most important thing to do, is really focus their memory on what that smell is supposed to smell like to them. Your olfactory cortex is right next to your memory center in the brain, and it's integrally connected, and we are actually utilizing that, reinforcing that synaptic connectivity by doing this type of training.
There's functional MRI evidence showing that before you do olfactory training, if you give someone with smell loss an odor, there's just this kind of disparate chaotic array of connectivity lighting up in the brain. If you do training and then again present that odor and functional MR, just the olfactory cortex lights up right where it's supposed to, and that really shows that you are changing synaptic connectivity by doing this. It's not just some silly woohoo aromatherapy type thing that's happening.
We are actually exercising the smell system, and I explain it to patients, and I think this actually resonates very well with people. They can understand this intuitively much better when you say this. If you had a stroke and you lost function of your arm, you would go to physical therapy and exercise that arm until you got that function back. You're doing the same exact thing with your smell system when you do olfactory training, so people really understand that. They say, "Oh, yes, that makes a lot of sense," then they're motivated to actually do it. As far as the odors, you start with those four, and then yes, at one month and then again at three months, I have people switch up these odors.
If the listeners want to, I think you just Google or search on the internet for the JAMA Otolaryngology patient education page I wrote about olfactory training, and it gives some examples of other combinations of odors that you can switch up to at one in three months. I just have that JAMA education page printed out in my office and I just hand that to patients. It goes over the entire thing of olfactory training and it shows those other odors that you can start with and then switch to. So it really gives all the information to them right there.
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Nutritional Supplements for Smell Loss: Evidence-Based or Purely Aspirational?
Apart from high-dose omega-3 fatty acids, no nutritional supplements produce convincing evidence in treatment of smell loss. Twice-daily, high-dose (1000mg) omega-3 fatty acid supplements reduced rates of smell loss in a randomized controlled trial of patients undergoing endoscopic skull base surgery. Evidence for vitamin A, zinc, and alpha-lipoic acid is limited. B vitamin supplementation can improve taste in patients with tongue-related taste issues but not smell loss.
[Dr. Gopi Shah]
Tell me a little bit, are there vitamins that help, or people taking B vitamins or anything like that to help? What are your thoughts on that?
[Dr. Zara Patel]
There are certainly a lot of things that people are taking, but not a lot of evidence for most of the things that people are taking. The top things that people ask me about are vitamin A, alpha-lipoic acid, vitamin B, zinc.
Just to give a kind of brief overview of those, there is actually good evidence that taking vitamin A orally does not have an impact on smell. There's no reason for people to take that. There may be benefit in intranasal application of vitamin A, but the data is not very strong. There's no placebo-controlled trial on that. Also, the formulation to get vitamin A into the nose that's not irritating and not damaging to mucociliary clearance, for example, we don't really have here in the US.
There's some data from other countries where they have different formulations, but I have not utilized that in my patients because we just don't have the right formulation here. Perhaps in the future, we will and maybe we'll have better data to support its use, but right now I don't have people use vitamin A and certainly not by mouth, that's not helpful.
As far as vitamin B goes, really the only data about vitamin B is when people actually have tongue issues, actual taste, like sweet, salty, bitter, umami, those things are damaged or gone. Sometimes there can be a vitamin B deficiency leading to that type of thing. Sometimes that can be helpful for specifically tongue-related taste issues, but no data really.
The one study that is out there showing oral zinc is helpful is in post-traumatic anosmia. In those patients, sometimes I'll say, "Yes, that's fine, you can try that," but in other patients, I don't really recommend it. I think maybe perhaps if we had a much better, well-done randomized control trial in the future, perhaps we might find some benefit, but right now there's conflicting data, and some suggesting it may be harmful, so I do not have people on zinc.
As far as alpha-lipoic acid, it's another one that has some interesting data and it does not have a randomized control trial that's well-controlled as far as timing of enrollments and controlling for spontaneous recovery and those types of things. Something that's an option for patients, but not something that I routinely prescribe just because of the quality of the studies and the methodologies.
Finally, omega-3. I actually ran a randomized control trial on a post-endoscopic skull-based surgery patient population looking at smell loss after that. That was 7 or 10 years ago that I was doing that, and there was a precipitous drop in the number of patients that had long-term smell loss after that surgery. These were patients who we were preserving the olfactory system very carefully, but likely just because of all of the post-operative inflammation, we're having smell issues.
Omega-3, a high dose omega-3, so 1,000 milligrams twice a day was highly impactful and helpful for those patients. My same protocol was just replicated in a study by Thomas Hummel in Germany in COVID-19 patients. It was also found to be helpful in that patient population. so high dose omega-3 is something that I do recommend for all my patients as well. The only people I wouldn't recommend it for are people who have an underlying bleeding disorder or are on other blood-thinning medications because it can thin your blood, especially at that dose.
Platelet-Rich Plasma (PRP) Therapy: A Novel Intervention with Promising Evidence for Loss of Smell
Utilized in various capacities, from facials to joint injections, platelet-rich plasma (PRP) shows promise in stimulating smell recovery amongst patients with post-viral smell loss. Injected into the olfactory cleft, platelet-rich plasma contains growth factors from the patient’s own blood plasma that stimulate regrowth of olfactory neurons. While further study is needed for PRP to become standard of care, a randomized controlled trial run by Dr. Patel demonstrated that patients with COVID-19 smell loss were twelve times as likely to recover olfactory abilities when treated with PRP versus a placebo injection. Since PRP uses material from the patient’s own body, no absolute contraindications exist.
[Dr. Gopi Shah]
All right. Let's get into the platelet-rich plasma. Just for our audience, I had to get the PRP initials correct. I think I called it protein-rich platelets, which doesn't even make sense. Just for anybody who was with me on the initials, platelet-rich plasma. Tell us a little bit about PRP.
[Dr. Zara Patel]
I first became interested in PRP, again, prior to the pandemic, I was starting to read a lot in the other medical fields, other literature about how it was being used. People are most familiar with it from orthopedic surgery where people will use PRP injections into knee joints and things like that to help with mild arthritis for cartilage regeneration. People use it in aesthetics, they get facials with the PRP injected into their face, like the vampire facial is what it's called. People inject into the scalp to regrow the hair.
PRP is really used all over the body. It's because all tissue in our body does use growth factors. PRP is when you draw someone's blood, you put it in a centrifuge, you spin it down, and all of the red blood cells, white blood cells, all that part of the blood goes off. What you're left with is this very platelet-rich and growth factor-rich portion of the plasma. Growth factors are used in the tissues all over our body to help regenerate.
The idea is really just that you are concentrating that and putting it right into the area that you need it most. Some people will kind of be suspicious of something that seems to be helpful no matter where you use it, no matter what you use it for. I was also kind of suspicious when I first started reading about it. It seemed like almost too good to be true or kind of woo-woo-type stuff, something that you could easily just charge for, and it might not have a lot of good data.
I was actually very cautious when I first started looking into it. I first ran a pilot study just to see, is this safe? Is this feasible for me to numb people up enough to inject something into their olfactory clefts and them not be bothered or uncomfortable? I did show that in my pilot study, again, prior to the pandemic. I did see a significant enough change in threshold in those patients that I thought, "Oh, maybe this is actually worthwhile studying in a true randomized control trial fashion."
Then the pandemic hit. I pivoted and made it specifically for COVID-19 smell loss. I ran this randomized control trial where I either injected patients with PRP in their olfactory cleft, or I did a sham placebo injection with saline. In that study, basically, the results were that the PRP arm had a greater than 12 times odds of more likely able to improve smell versus the placebo arm.
It didn't help everybody. Again, it wasn't some magic thing where people the next day said, "Oh, I smell normally again." These were incremental changes, different amounts in everybody, but it was a significant improvement. The most important thing is really that the improvement was a change in MCID, so minimally clinically important difference. Not just, "Oh, yeah, some numbers moved," but the amount of numbers that moved was the MCID for that particular test, the Simmons-Dix test that I was using.
[Dr. Gopi Shah]
What makes somebody a candidate, and when do you start considering?
[Dr. Zara Patel]
I would say everyone's a candidate at this point. I'll harken back to what I said multiple times, that the duration of loss before definitive intervention is one of the major prognostic factors in how much we can bring back. Certainly, in a trial setting, in that randomized control trial, I did not enroll anyone before six months because I didn't want spontaneous recovery to confound my results of my intervention, but off-study, of course, as soon as you can get patients some intervention that's going to possibly help them, the sooner the better.
In the trial, I also had people already try and fail to improve on things like olfactory training and budesonide irrigations because again, when I do a study, I want to make sure I'm actually significantly contributing to our literature of what more, what is going to help people even more than what we've already showed before. I don't want to just show some equivalence to things that we're already doing that are just a little bit better here and there.
These were people who improved, people who had already failed olfactory training and budesonide irrigation, but again, now that we're off-study, if I see a patient, I tell them about everything, and I would want them to do everything as soon as possible right away. Why hold something back when we know that time is brain, time is nerve? The longer you go, the less likely you are able to get that back.
Dr. Zara Patel
Dr. Zara Patel is director of endoscopic skull base surgery and a professor of otolaryngology and neurosurgery at Stanford in California.
Dr. Gopi Shah
Dr. Gopi Shah is a practicing ENT at UT Southwestern Medical Center in Dallas, TX.
Cite This Podcast
BackTable, LLC (Producer). (2023, August 1). Ep. 122 – Evaluation & Management of Patients with Olfactory Dysfunction [Audio podcast]. Retrieved from https://www.backtable.com
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