NSAID Allergy Ups Risk for Opioid Abuse in Osteoarthritis

November 23, 2020

Patients with osteoarthritis and an allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) are more likely to become addicted to opioids than nonallergic patients, according to a 5-year retrospective analysis.

In fact, the risk of developing an opioid addition is twice as high in those with an NSAID allergy as in those without. "We found that NSAID allergy might be an important risk factor for opioid use disorder," said investigator Lily Li, MD, from Brigham and Women's Hospital in Boston.

But it appears that not all reactions reported in an electronic health record indicate that a patient is "truly hypersensitive" or allergic, she said during her presentation at the American College of Allergy, Asthma & Immunology 2020 Annual Scientific Meeting, where the oral abstract won second place in the Clemens von Pirquet award.

"Over 80% of reported reactions are actually thought to represent nonallergic side effects and intolerances," Li explained. When tested in a lab, "we know that confirmatory drug challenge is often negative," she added. "Many patients labeled NSAID-allergic may actually be able to tolerate NSAIDs."

Many patients labeled NSAID-allergic may actually be able to tolerate NSAIDs.

Li and her colleagues set out to evaluate the potential risk for opioid addiction in NSAID-allergic osteoarthritis patients because opioids are often prescribed to patients with a history of NSAID allergy.

"The opioid epidemic remains a pressing health issue," she said. More than 2 million Americans are addicted to opioids, and "seven out of ten opioid prescriptions are written for relief of physical pain." This is contrary to the fact that NSAIDs are indicated for musculoskeletal pain by the World Health Organization.

The team searched the electronic health records of adults with osteoarthritis treated in a tertiary care center from January 2013 to December 2018 and identified 15,682 patients with osteoarthritis. Of these, 1442 (9.2%) patients had 1856 NSAID reactions documented in the allergy tab of their electronic health record.

The most common reaction reported was to aspirin (25.6%), followed by ibuprofen (12.6%), naproxen (11.5%), celecoxib (5.7%), and "other NSAID medication" (7.4%). Reaction to NSAIDs "as a class" was reported in 22.3% of cases, and reaction to other NSAIDs — specifically, indomethacin, rofecoxib, diclofenac, nabumetone, and ketorolac — was reported in less than 5% of the cases.

Not all reactions were "allergic", however.

Of the 1856 reactions documented, hypersensitivity reactions were reported in 656 cases (35.3%), with rash and angioedema or swelling being the most common. Adverse effects related to the medication were reported in 749 (40.4%) cases, the most common being gastrointestinal upset, nausea, dizziness, and headache. In nearly one-quarter (24.3%) of the records reporting NSAID allergy, no specific reaction was documented.

This is an indication that further testing might be warranted to confirm NSAID allergy. "The high percentage of 'unknown' or 'other' reactions highlights the challenges of evaluating and caring for patients with unclear reaction histories," said Li. "This warrants clarification."

Higher Odds of Opioid Use Disorder

The 1442 patients with a documented reaction were matched with 5766 patients with a documented non-NSAID allergy for baseline comorbidities, including cardiovascular disease, renal insufficiency, connective tissue disease, peptic ulcer disease, anxiety, depression, malignancy, chronic urticaria, allergic rhinitis, asthma, and atopic dermatitis.

When NSAID-reactive patients were compared with the 14,240 patients in the osteoarthritis cohort without documented allergy, NSAID reaction was shown to increase the odds of opioid use disorder significantly (odds ratio [OR], 2.09).

Opioid use disorder was also higher in the NSAID-reactive group than in the propensity-matched group with non-NSAID allergy (OR, 1.56).

In multivariable regression models adjusted for baseline patient characteristics, NSAID-reactive patients were still more likely to develop opioid use disorder than those in the osteoarthritis cohort without documented NSAID allergy (OR, 1.70) and than in those with non-NSAID allergy (OR, 1.53).

"This supports our hypothesis," Li confirmed. Other factors also conferred a higher risk for opioid use disorder, including being younger, being male, and having Medicaid or Medicare rather than private insurance, depression, or asthma.

An NSAID reaction increased the odds of an opioid prescription (OR, 1.23), but lowered the odds of a celecoxib prescription (OR, 0.77). "This indicates overprescribing of opioids and underprescribing of celecoxib," Li explained.

"While celecoxib is considered an NSAID," she noted, "due to its selectivity as a cyclooxygenase-2 [COX-2] inhibitor, it has little cross-reactivity with non-selective NSAIDs. It can almost always be used safely, even for patients with confirmed hypersensitivity to nonselective NSAIDS."

Overdiagnosis of drug allergy is a significant clinical — but also social and economic — problem.

"Overdiagnosis of drug allergy is a significant clinical — but also social and economic — problem," said Marek L. Kowalski, MD, PhD, from the Medical University of Lodz in Poland.

The increased frequency of opioid prescription probably results from avoidance of all NSAIDs, which are first-line analgesics in osteoarthritis patients, Kowalski told Medscape Medical News. "Awareness of the NSAID labeling problem is important since a significant proportion of these patients, probably up to 50%, are not truly allergic to NSAIDs."

Kowalski said he agrees that alternative pain medication can be prescribed. "A well-trained allergist may offer an alternative analgesic, which will be well tolerated by a patient, thus decreasing overall opioid use."

Li and Kowalski have disclosed no relevant financial relationships.

American College of Allergy, Asthma & Immunology (ACAAI) 2020 Annual Scientific Meeting. Abstract A003.

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