Common Sense – Common Cents – Common Scents
I go with #3 because something just doesn’t smell right.
Now we have people wondering if there are any safe medications at all for managing pain?
Almost three years to the day an “anti-opioid” group petitioned the FDA for major changes to the FDA approved opioid labeling. That small snowball propagated much discussion in professional journals and the lay press with significant momentum for almost 14 months until finally the snowball melted away by the Agency’s final decision. Nonetheless, an avalanche against rational opioid use still hovers over legitimate patients. Third party payers are making policies based on fear, ignorance, and profit (common cents), while politicians continue to use that fear as a bully pulpit to gain popularity without considering the real patient centric issues.
It is becoming noticeably more difficult for patients to find clinicians that are willing to prescribe chronic opioid therapy even to the most medically justified of non-cancer patients suffering intractable chronic daily pain. In essence, “the damage done by the war on opioids” has caused the pendulum too swing too far.
Joining me today for this timely post is 2016 Western New England University College of Pharmacy Candidate, Phillip Boglisch.
Two years following the initial hoopla, the opioid story has now become the backdrop to a July 9th FDA announcement that requires stronger warnings for non-steroidal anti-inflammatory drugs (NSAIDs) due to the risk of heart attack and stroke. Personally, we have no problem with that, as we all should exercise caution when prescribing and dispensing any medications – safety is tantamount to any of the medical professions. But, somewhere along the way, the train has fallen off the track. Each day it seems more and more that clinicians are left with fewer pain medication options laden with algorithms, third party payer policies, institutional guidelines, and various other “standards”, all of which are important, but none of which should replace common sense. Patients need to be treated as individuals, not as a speck of dust within a universe of templates.
In the Agency’s effort to expose an important warning against NSAIDs, they may have left out a very important agenda item – common sense. Specifically, do topical NSAIDs demand the same class wide warnings regarding heart attack and stroke levied against their oral counterparts? And if they do, where is the evidence to support that any topical NSAID is as dangerous as any corresponding oral drug in the at-risk-patient?
Over three years ago Dr. Stewart Leavitt provided a nice overview citing various studies where he pointed out that “Direct comparisons of any topical NSAIDs with an oral NSAID formulation did not show any differences in efficacy. There was an increase in local adverse effects (mostly mild skin reactions) with topical NSAIDs compared with placebo or oral NSAIDs, but no increase in serious adverse events.”
Let’s look first at another issue that has been largely ignored.
Aspirin is not a steroid. In adequate doses aspirin is an anti-inflammatory. Therefore it follows that aspirin is a non-steroidal-anti-inflammatory. Right? Well, maybe, but it’s not so simple, because unlike “traditional NSAIDs” (i.e. ibuprofen and naproxen), aspirin causes irreversible platelet binding which blocks clotting activity for the life of the platelet. That is not the case for traditional NSAIDs, as their effect on platelets is “reversible” In short, when the NSAID half-life has terminated, the platelets will still work to cause clotting. And of course for this reason, low dose aspirin is actually protective against heart attack and stroke for these reasons. So although all of these are NSAIDs, they are not the same, nor do they have the same perils. It follows therefore that the risk of heart attack and stroke are not likely risks of topical salicylates and the newer stringent warnings have not been assigned to topical salicylates or topical steroids. We can live with that. But we can’t say the same for topical steroids (i.e. hydrocortisone, dexamethasone, triamcinolone), although that is a topic for another day.
So okay, yes, perhaps topical salicylate products such as Aspercreme, Bengay, Icy Hot, Salonpas and others shouldn’t carry these new NSAID warnings – it make sense. But, perhaps they need different warnings that for the most part are absent.
Consider this…
Where are the FDA “strong” warnings about the potential dangers of aspirin-based topical products causing harm or death? A 17 year old track star died from applying various topical products containing methyl salicylate just a few years back. Dr. Thomas Kearney, director of a California poison control center, states “It’s on my one-swallow-to-kill list for kids.” A 16 month old needed to spend 1 week in the intensive care unit due to salicylate toxicity after ingesting an unknown quantity of salicylate massage oil causing vomiting and generalized tonic-clonic seizures.[1]
Topical Options and Practical Considerations
And now for the finale! Perhaps patients should not be denied topical NSAIDs as a therapeutic option especially considering the diminished choices these days. To the best of our knowledge, there have never been reports of any toxic effects from any topical NSAID, as Taylor Swift puts it in her song, “LIKE EVER”. The topical NSAIDs (i.e. diclofenac, ketoprofen, and naproxen) have very limited or unmeasurable systemic absorption – for this there is evidence.
From a more comprehensive scientific and pharmacokinetic perspective, we published a piece outlining the various commercially available topical NSAIDs in Pharmacy Times entitled “Should Topical NSAIDs Have Strict Heart Risk Warnings?” In short, at FDA approved doses, none of them have been shown to achieve blood levels sufficient enough to merit the previous, and certainly not the newer templated NSAID warnings.
By way of example, below is a table that compares the various commercially available dosage forms of topical diclofenac, the most commonest of all NSAIDs used worldwide. Note that the 50mg tablets taken 3 times daily has an average maximum blood concentration (Cmax) of 2270ng/mL. In general, the higher a Cmax, the greater is an expected toxicity risk. When comparing the Cmax of all the topical formulations, it becomes quite clear that topical diclofenac yields but a fraction of the oral counterpart in FDA approved diclofenac doses.
|
Diclofenac Dosage Forms |
||||
|
Brand Name |
Dosage Form | Strength | Dose | Cmax (ng/mL) |
| Flector 2 | Patch | 1.3% |
Applied twice a day for 5 days |
1.3 – 8.8 |
| Pennsaid 3 | Topical Solution |
1.5% |
Applied 4 times daily for 7 days | 19.4 ± 9.3 |
|
Voltaren Ophthamic 4 |
Ophthalmic Drops | 0.1% | Instilled 2 drops every 4hours |
<10 |
|
Diclofenac |
Tablets | 50mg | Taken 3 times daily | 2270 ± 778 |
| Voltaren 5 |
Gel |
1% |
Applied 48g/day* |
53.8 ± 32 |
| Solaraze 6 |
Gel |
3% |
Applied 2g 3 times daily for 6 days |
5±5 |
|
* This is above the max daily dose recommended |
||||
Reformatted from “Should Topical NSAIDs Have Strict Heart Risk Warnings“, Pharmacy Times July 2015
Perhaps the most bizarre example is diclofenac ophthalmic drops, where blood levels after therapeutic doses were immeasurable.[4]
To summarize, all topical diclofenac dosage formulations delivery result in only a small fraction of the diclofenac actually reaching the systemic circulation compared to the oral route.
The FDA does admit that “newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID”, which is why they state that NSAIDs may have an “increased risk range from 10 percent to 50 percent or more.”
Maybe the FDA should require topical NSAIDs to state that there is no evidence to support topical products carry the same risks as orally administered products.
In our minds, patients have been tormented enough. There is nothing to be gained by needlessly scaring patients about unfounded risks of topical NSAIDs which might preclude frightened patients from using a potentially effective option such as topical diclofenac gel or other similar products.
Maybe the FDA should ensure that all topical salicylates carry hefty warnings for possible death if ingested orally or used in amounts substantially greater than recommended.
Maybe adding these new NSAID warnings to topical products will curtail clinicians from treating any pain problems with medication, since opioids and acetaminophen also have inherent risks.
Maybe we need to use common sense, be practical, and keep repeating the old adage “absence of evidence is not evidence of absence”, LIKE EVER!
As always, comments welcomed!
This article was collaboratively written with Phillip Boglisch, a 2016 PharmD candidate at the Western New England University College of Pharmacy in Springfield, MA and an MBA candidate with expected conferment, fall semester 2015 at WNEU College of Business. He completed his undergraduate degree at Clark University in Worcester, MA where he obtained a BA in Chemistry in 2012. Phillip is interested completing a PGY1 and possibly a PGY2 residency. He is currently under the mentorship of Dr. Fudin studying pain management.
References
- Muniady RK, Sinnathamby V. Salicylate toxicity from ingestion of traditional massage oil. BMJ Case Rep. 2012; Aug 24.
- Flector [package insert]. Bristol, TN: King Pharmaceuticals, Inc.; 2012.
- Pennsaid [package insert]. Hazelwood, MO: Mallinckrodt, Inc.; 2013.
- Voltaren Opthamic [package insert]. Fort Worth, TX: Novartis Pharmaceutical Corporation; 2012.
- Voltaren [package insert]. Parsippany, NJ: Endo Pharmaceuticals, Inc.; 2014.
- Solaraze [package insert]. Melville, NY: PharmaDerm; 2012.
Thank you, Dr. fudin!
Somehow, I had missed this post. I have seen first hand what overprescribing of NSAIDS will do. My poor aunt, who had debilitating Osteoarthritis and late stage Osteoporosis was refused anything “stronger” for pain, like an opioid, and was prescribed high doses of NSAID oral medications, even after she developed THREE bleeding ulcers. She ended up having a stroke, going into a nursing home, and draining her life savings of over $500,000.00. Literally, the LAST month of payment came, and she died. She would have preferred to live in LESS PAIN, without the bleeding ulcers, the massive stroke, and painful, slow death. She also would have preferred to leave some money to her sister (my mom), and her niece (me). At least she wasn’t aware of all this at the end, because it would have broken her heart, too.
My question is this… My Mom was recently started on Eliquis (5mg twice a day), for A-Fib that developed because her doctor was too lazy to call her Cardizem in to the pharmacy for a week, and she went without it. (Don’t get me started). I am learning how little some doctors actually CARE about not just “pain patients”, but elderly, sweet, compliant, do-not-ever question the doctor ones, too. I’m trying to learn more about some of her meds, and some contraindicated ones. She was told to STAY on her baby 81 mg. aspirin, and was also told she could continue to use Voltaren gel on her hands, etc… , as much as she needed. I was the one who told her “no more” Aleve, Advil, etc… She is also always in pain! Lupus, Sjogrens, and (not officially) diagnosed Ehlers-danlos Syndrome, with two detached retinas (no laser surgeries, full buckle behind eye), a lense dislocation, enlarged aortic roots, MVP, poor wound healing, joint dislocations, high myopia, blue sclera, high arched pallet & tooth crowding, hypermobility, joint pain, bad OA, and Osterporosis, and a whole host of other typical EDS symptoms. Her hand OA is very painful & she does get some relief from Voltaren Gel. She doesn’t take anything else for pain, as Tylenol does NOTHING to touch it, and oral NSAIDS are off the table now. It seems to me, with her regular use of topical Voltaren gel, combined with 81mg. aspirin, AND Eliquis at 5mg, both am & pm, couldn’t even that small absorption be a risk??? I know you are not her doctor, but, let’s face it, neither is HER doctor!
Thanks for this post & for everything you do!
Nancy
doctors have been sued for over prescribing oral pain medication. doctors have been sued for under prescribing oral pain medication. With the FDA new warning, any patient being treated with oral pain medication or topical medication suggests that the doctor “MAY” be putting you at risk. Perhaps the FDA should do a study to see if you pray the rosary has adverse effects. the FDA is so forewarning as to what is hazardous, they are putting patients at risk for NOT being treated. Some common sense, rational approach to oral and topical care, as well as adjunct treatment, therapies, etc are necessary. The FDA wants to prevent anybody from having an adverse effect by avoiding treatment. Well, with their logic, if a patient never had surgery, they’d never have a post-op infection. They never address medical necessity, proper treatment and unavoidable potential complications since we all are different.
Each case is individual. What is left if they take topical analgesics away? How about this… the patient tells the physician this particular product causes ____, the physician says, “Well, lets try something different to see if your body tolerates it. One size does not fit all.
An emergency physician I worked with for years cautioned against the use of a heating pad over topical analgesics, such as OTC preparations (Bengay, Icy Hot, etc) saying heat could increase systemic absorption and the risk of blood dyscrasias I don’t know his source of information, but I headed his warnings personally, because the man was a walking encyclopedia. Common sense says heat dilates pores so there would be greater risk for capillary transfer.
While I appreciate the evidence regarding ingestion of NSAIDS and CV risk, what you report here for topicals pales by comparison. As a side note, people die from GI bleeds too. As an RN with many years experience in the emergency department (CEN, TNCC) and intensive care I have seen what NSAIDS can do. I will never forget the man who came in with a full blown GI bleed, pumping blood in was not fast enough for the volume he was losing. His family member reported that he was taking Alka-Seltzer for his stomach ache.
You are absolutely right about classifying ASA as an NSAID as though it were the same as ibuprofen, etc. It implies they are same and as you say, they do not.
To add a warning to topical analgesics for CV risks without evidence to support it only speaks to a lack of common sense. Where does the FDA develop their standards? It seems their attitude for most all they do is– if one snake is venomous, all snakes are.
Excellent points Jeff and Phillip. I am particularly concerned about the increasingly diminishing options for the elderly in chronic pain – to further narrow options by potentially excluding low systemic absorption, safe and effective NSAID topicals by painting them with a broad “ADE risk” brushstroke is terrible. And, if you want to follow the ultimate thought experiment on this topic, a potential discrimination against a vulnerable population. I support a change in labeling regarding a lack of evidence to support the new warnings for topical products.
Good point Anne, and not all elderly metabolize medications the same either. I have known folks in their 80’s to tolerate opioids, for instance, quite well and others that cannot tolerate a fraction of the recommended dose.
Jeff and Phil- without your thorough investigation and publishing of this information, many providers would avoid this route of admin for NSAIDs in their patients with cardiac disease. Before you know it capsaicin will be a target! Your information is compelling enough for me to go ahead and recommend its use in patients who would benefit from an NSAID. THANK YOU!
your my fav genious
Thank you Melissa – I’m going to print that comment and share it with my kids.
Yes Jeffrey we are usually wrong when we paint all dugs in a class with the same brush. You have astutely illustrated a flaw in the recent warning. I am sure the FDA would welcome a polite letter suggesting they reconsider the blanket warning but be more precise with their warning. The good thing is that the FDA was willing to step up and point out that even NSAIDs have serious risk associated with their use. When treating pain we have to be cognizant of all treatment options and their potential side effects. No therapy is without side effect but lack of treatment can also have untoward consequences.
Well don again Jeffrey.
I love that you included pharmacokinetic data in this blog. It makes things so crystal clear! Thank you for posting this!
Nice to hear from you Dr. Perkins, especially since you are the “kinetics kween”. I should have contacted you for the Pharmacy Times article because I know that tables are your specialty!
Plop, plop, fizz, fizz……….Oh what a relief this is! The commentary is an evidence-based, common sense breath of fresh air. It’s just NOT that complicated, and Dr. Fudin is clear in his delineation of what is clinically-relevant and what simply isn’t. This very question arose in clinic last week and I am so grateful for the intelligent, down-to-earth response. But that we could have publications this clear in many more decision-making domains!
Thank you Dr. Brackett Perhaps if enough clinicians comment it would be worthwhile petitioning the FDA to consider these common sense changes to the packaging. I pledge to lead the cause of enough folks show interest.