Anti-Inflammatory Side-Effects Carry High Price Tag

Anti-inflammatory drugs hold the top spot for specialty drug spending, accounting for 23% of all dollars spent on pills 0specialty medications.

Unfortunately, these drugs are among the most common culprits when it comes to adverse effects, and those end up costing us billions—$2.2 billion from 2010-2014 to be exact.

Those data come from a joint report entitled, The Cost and Impact of Adverse Events: Anti-Inflammatory Drugs,published by Advera Health Analytics and Atlantic Information Services.

Advera, a California-based healthcare informatics company that analyzes post-marketing drug side-effect data to improve patient safety, and Atlantic, a DC-based hospital industry publisher, teamed up to compile and analyze mountains of post-market data from the FDA’s Adverse Event Reporting System to calculate the adverse event burden of seven of the most commonly prescribed anti-inflammatories: Cimiza, Enbrel, Humira, Otezla, Remicade, Simponi, and Stelara.

The findings are troubling.

According to the report, side effects from these drugs cost the healthcare system roughly $368 million per year, adding an average of 2.4% to the cost of covering these drugs. The financial statistics, though alarming, do not capture the dimension of additional human suffering experienced by people who seek relief from chronic inflammatory diseases, but find that their problems are only complicated by adverse drug effects.

Use of these seven drugs is soaring. The report estimates that in 2014, there was an 8.5% increase in prescriptions over the previous year. The surge is being driven by conditions such as rheumatoid arthritis and Crohn’s, which are on the rise across the nation.

New guidelines limiting the use of opioid drugs are also playing a role, as practitioners increasingly turn to anti-inflammatories rather than opioids to help attenuate patients’ pain.

“Unlabeled,” Yet Costly

The Advera/Atlantic report is directed at insurance industry executives, however, its content is equally pertinent to primary care practitioners as it discusses both the most common side effects and many less frequent but more costly conditions resulting from anti-inflammatory prescriptions.

advera health transparentInterestingly, the authors report that for the five costliest side effects identified for each of the seven drugs, about 24% of the total cost is attributable to “unlabeled adverse events” — side effects that are not formally recognized or disclosed on the drugs’ warning labels and can be discovered only by mining post-market data.

Take staphylococcal infections as an example. They’re not typically thought of as an adverse effect of anti-inflammatory use, and there’s no mention of this possibility on the drug labels. But they are linked, and they occur more frequently than many physicians realize.

Advera estimates these infections, secondary to use of anti-inflammtories, cost health plans over $50 million from 2010 to 2014, making it the costliest side effect associated with this drug class.

Stats like this highlight the need for careful study of post-market data from independent sources rather than relying exclusively on clinical trials data provided by drug makers.

The authors report that psoriasis currently affects some 7.5 million individuals in the US alone, while Rheumatoid arthritis and Crohn’s disease each affecting approximately 1.6 million. Furthermore, the Crohn’s and Colitis Foundation of America reports that an additional 70,000 individuals are diagnosed every year.

Because of the debilitating and progressive nature of these and other inflammatory conditions, people with only moderate symptoms are typically eager to begin treatment. Unfortunately, physicians often lack complete information regarding the side effects associated with certain drugs.

For instance, the Advera/Atlantic report notes that, “drug label inserts are generally created based on clinical trail data, but such data are often associated with serious publication bias issues. Furthermore, a Journal of the American Medical Association study of more than 100 clinical trials found that 65% of harms outcomes were incompletely reported”.

The FDA’s FAERS archive contains useful information about real-world experiences with drugs. However, accessing this information is often a complex, time-consuming process. All the data utilized for this study is sourced from FAERS reports logged between January 2010 and September 2014, and then consolidated for ease of meaningful analysis.

Diverse Mechanisms

The various anti-inflammatory drugs are often used interchangeably, but they do not all have the same mechanism of action, and the distinctions are important.

The majority of anti-inflammatories are TNF blockers, but others function by inhibiting certain cytokines or enzymes. The Advera/Atlantic authors reviewed side effects for each drug with specific attention to mechanisms of action.

Of particular interest was a list of the five highest reporting odds ratios (ROR) for non-disease related adverse effects. A value greater than 1 indicates a higher than expected reporting rate for a given adverse effect.

TNF Blockers:TNF blockers like Remicade, Enbrel, Humira, Cimzia and Simponi make up the largest category of anti-inflammatory meds, with Humira and Enbrel at the top, accounting for 80% of the market. These drugs function by blocking the action of TNF, which is commonly elevated in inflammatory conditions such as Crohn’s.

The most common complaint about both Humira and Enbrel is injection-site pain; Enbrel has the highest ROR (19.15) for this effect, followed by Humira (13.69). Both have comparable rates of less frequent but serious events like staph infection and myocardial infarction (Enbrel does not label myocardial infarction).

While Humira and Enbrel are fairly similar, when it comes to the top five RORs for each some differences begin to appear. Humira’s top five were: injection site papule (189.70), intestinal fibrosis (not labeled [123.51]), intestinal fistula infection (49.04), synoviothesis (35.94) and stoma site pain (not labeled [33.54]).

Enbrel’s top five RORs were: injection site recall reaction (1,160.71), injection site warmth (71.75), injection site macule (53.44), injection site swelling (42.48) and injection site pruritus (35.57).

Simponi is a relatively new option; at the time of publishing there were only two years’ worth of post-market data for the drug. It confers the highest risk of pneumonia compared with other drugs in this class. It was ranked second for the development of cellulitis, behind Stelara. Also of note, myocardial infarction, though not common, was a serious possible side effect not listed on Simponi’s label.

Overall, the TNF blocker side-effects with the highest RORs were: cell marker increase (81.21, not labeled), post-injection reaction (63.36), tuberculosis pleurisy (35.88), latent tuberculosis (35.51), and intervertebral discitis (23.48).

Cimzia, when compared to the other seven drugs, showed high rates of abdominal pain and fatigue. Specifically, fatigue was the most frequently reported complaint, followed by abdominal pain and nausea (not labeled). The top five highest RORs were: non-infective bronchitis (490.13), ileocolectomy (not labeled [72.56]), rectal abscess (47.03), perineal abscess (33.05) and frequent bowel movements (not labeled [32.14]).

“Infusion-related reaction” was the most prevalent side effect of Remicade, but vomiting also was frequently reported.

Several TNF blockers carry significant risk of intestinal perforation. Remicade had the highest ROR for this side-effect (3.34), followed by Cimzia (2.81).

Cytokine Inhibitors Rather than blocking TNF, Stelara down-regulates inflammation by specifically binding to the p40 protein subunit found on both interleukin (IL)-12 and IL-23. This, in turn, lowers the rate of natural killer cell activation.

Commonly reported side effects for Stelara included cellulitis and latent tuberculosis. The number of cellulitis reports was comparable to other drugs in the class. However, out of the seven drugs reviewed, Stelara had a significantly higher ROR for latent tuberculosis (116.82). Tuberculosis RORs for the other six drugs ranged from 7 to 36. The top five highest Stelara RORs were: mycobacterium tuberculosis (126.51), latent tuberculosis (116.82), cholangiocarcinoma (44.05), malignant melanoma in situ (43.35), and keratoacanthoma (32.13).

Enzyme Inhibitors Otezla reduces inflammation by inhibiting the intercellular enzyme PDE4. It was the newest drug evaluated in the Advera/Atlantic study, with only nine months’ worth of data available.

Otezla is a promising new option, both because it has the lowest price point of the seven, and because of its ease of use: it is a pill not an injection.

Most of Otezla’s reported side effects are minor (diarrhea, nausea and headache) though statistically important because they were reported more frequently than in the other six drugs.

For example, Otezla has an ROR for diarrhea of 15.83 while the next closest ROR was only 1.91; it’s ROR for headache is 7.47 while all others fall below an ROR of 2.0.

However, Otezla had no reported incidence of more serious side effects common among other anti-inflammatories, such as cellulitis, dyspnea, intestinal perforation, latent tuberculosis, pneumonia and urinary tract infection.

Non-Rx Alternatives

The authors of the report underscore the importance of lifestyle changes, nutrition-based therapies, and holistic healing modalities in attenuating chronic systemic inflammation, and reducing the need for risk-laden prescription drugs.

They cite a 2015 study from Yale School of Medicine showing that beta-hydroxybutyrate (BHB) an endogenous compound produced during fasting inhibits NLRP3, which drives inflammation (Youm YH, et al. Nature Medicine. 2015: 21; 263-269)

Researchers found that BHB can be produced by any of the following: intermittent fasting, high-intensity exercise, calorie restriction or a low-carbohydrate ketogenic diet.

While many patients suffering from inflammatory conditions may not be able to undertake high-intensity exerciseacupuncture, low-carb diet or intermittent fasting may prove helpful for them. Practitioners should also consider recommending diets high in anti-inflammatory foods and spices, such as omega-3 rich fish, flax, green tea, ginger, turmeric and cayenne.

Acupuncture can also play a role in mitigating inflammation. In 2014, the World Journal of Gastroenterology published a trial of moxibustion acupuncture in individuals suffering from Crohn’s disease. The study involved 92 medication-treated patients with CD Activity Index (CDAI) scores ranging from 151 to 350. Participants were randomly divided into either a treatment or control group. All patients were blinded during the trail and maintained whatever drug regimens they were following prior to enrollment.

Patients in both groups came for treatment thrice weekly for 12 weeks. The active treatment group received acupuncture based on TCM principles, using moxibustion with mugwort. The control group received superficial acupuncture at non-meridian, non-acupoint zones and faux moxibustion with wheat bran.

After 12 weeks, 70% of the treatment group had dropped their CDAI scores by more than 100 points; only 14% the control group showed reductions of 100 points or more. Follow up observations at 24 weeks found that those treated with true acupuncture had more stable long-term inflammation relief than those receiving sham treatment (Bao, Chun-Hui et al. World Journal of Gastroenterology: 2014; 11000–11011).

The challenge of assuaging chronic pain and inflammation without introducing new risks is a delicate balancing act to be sure. Pharmaceutical scientists are certainly doing their part to improve the quality and safety of anti-inflammatory drugs. Newer meds like Otezla are definitely less risky than older ones.

Otezla far outranked its competitors for both safety and affordability. However the authors note that, “although there are few signals for serious safety concerns to date, caution must still be taken given its relatively unproven post-market experience when compared to Remicade, Humira and Enbrel”. Of those three, Enbrel had the fewest serious side effects and lowest overall cost associated with adverse effects.

One new drug, not included in the review, which the authors suggest keeping an eye out for is Cosentyx; it is poised to compete with Stelara as a once monthly treatment option.

Still, pharmaceutical solutions are expensive, as is clearly demonstrated in this report, and they do little to resolve the fundamental physiological imbalances driving chronic inflammatory states. In this context, the glaring need for practitioners who can bring a comprehensive holistic approach has never been more clear.


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