Exacerbation of asthma secondary to fentanyl transdermal patch

Abstract

Asthma is a common chronic inflammatory disorder of the airways associated with hyperresponsiveness, reversible airflow limitation and respiratory symptoms.¹ All patients with asthma are at risk for exacerbations that may range from mild to life threatening. Different triggers cause asthma exacerbation by inducing airway inflammation and/or provoking bronchospasm. Allergen-induced bronchospasm results from IgE-dependent release of mediators including histamine, prostaglandins and leukotrienes.² Opiates are commonly used to treat chronic pain.³ Although hypersensitivity to opiates or accumulation of opiates can cause respiratory depression, opiates are also used in the management of cough and dyspnoea associated with advanced COPD and heart failure.^4,5 Here, a report is presented on a patient who developed persistent exacerbation of underlying stable asthma after initiating fentanyl transdermal therapy for chronic low back pain. He underwent extensive investigations and a detailed reassessment of history, especially medication history, led to the possible causative factor; once recognised, removal of the offending agent (fenatnyl) resulted in complete improvement in his symptoms within 72 h.

BACKGROUND

Asthma is common and so are its exacerbations that may range from mild to life threatening. Different triggers cause asthma exacerbation by inducing airway inflammation and/or provoking bronchospasm. Opiates are commonly used to treat chronic pain. Although hypersensitivity to opiates or accumulation of opiates can cause respiratory depression but opiates are also used in the management of cough and dyspnoea of advanced COPD and heart failure.^4,5 Fentanyl is contraindicated in acute or severe asthma but there is no specific contraindication of its use in stable asthma. In the present report, a transdermal fentanyl patch was given to a patient for chronic back pain and a few days later he started to have an exacerbation of symptoms; during initial assessment a mild infiltrate was noted on chest x ray that was felt to be the cause of the current exacerbation, and the patient initially did not mention the addition of fentanyl therapy. The onset of symptoms was a few days after starting transdermal fentanyl therapy, so association with fentanyl therapy was not considered by the patient. He continued to have persistent symptoms and negative work-up save for an increase in eosinophils. Because of the persistent symptoms after resolution of “pneumonitis” that was treated with for moxifloxacin 400 mg/day for 7 days and negative work-up, possibility of a drug reaction was considered and a detailed medication history was taken. Although anti-inflammatory agents may precipitate an asthma attack but the patient denied using it on a regular basis and the symptoms persisted after discontinuation of diclofenac. Fentanyl was felt to be responsible for this exacerbation based on circumstantial evidence and after discussion, a decision was made to stop the agent reluctantly by the patient and within 72 h his symptoms resolved and his condition returned to base line. The likelihood of exacerbation being secondary to a seasonal allergy is low, as symptoms resolved after stopping fentanyl therapy.

This is interesting because often we do not pay much attention to medication reaction as a cause unless the patient has skin rash, fever etc. A transdermal therapy that is not taken daily by the patient also is not often recalled by the patient as a medication. This case, once again, illustrates the importance of a detailed history in solving complex cases.

CASE PRESENTATION

A 43-year-old man with history of asthma since childhood had been reasonably stable over the years, save for occasional short-term exacerbation that responded fairly well to a short course of steroids. In February 2008, he presented with increasing shortness of breath and cough for a month. He was admitted with acute exacerbation of asthma, and a chest x ray revealed faint left basal infiltrate; it was felt that this episode of “pneumonitis” exacerbated his underlying asthma and was treated with antibiotics. Results as seen on chest x ray improved with antibiotics but he continued to have ongoing wheezing and shortness of breath and was discharged home on a course of oral azithromycin and prednisone 50 mg/day for a week.

He had been on theophylline (Theo-dur) 600 mg twice a day, salbutamol sulfate (Ventolin) two puffs four times a day as required, fluticasone/salmeterol (Advair diskus) 500 μg twice a day, montelukast sodium (Singulair) 10 mg/day, ketotifen fumarate (Zaditen) 20 mg/day and fluticasone propionate (Flonase) nasal spray.

His past medical history was remarkable for mechanical low back pain for which he had been on cyclobenzaprine 10 mg three times a day, acetaminophen 1 g three times a day as required, diclofenac/cytotec (Arthrotec) 75 mg as required and oxycodone/acetaminophen (Percocet) one tablet three times a day as required. Because of his ongoing symptoms of low back pain, transdermal fentanyl (Duragesic 50) 50 μg every 72 h was added to his therapy regime in January 2008.

He continued to have ongoing difficulty with breathing and audible wheeze, especially of upper airways. Further chest x rays remained normal, including a CT scan of the chest that failed to show any endobronchial or obstructive process. A pulmonary function test showed airway obstruction. Sputum cultures remained negative. He had no known allergies and denied any skin rashes or symptoms of joint pains, fever or chills. He denied symptoms of post nasal drip. He denied symptoms of heartburn or reflux. However, because of persistent and ongoing symptoms of “asthma exacerbation”, the possibility of reflux contributing to symptoms was entertained and he underwent gastroscopy that was also unremarkable except for mild gastritis; esomeprazole (Nexium) 40 mg/day was added to therapy.

Despite optimal bronchodilator therapy, antibiotics (moxifloxacin 400 mg/day for 7 days), three courses of oral prednisone, antireflux therapy, negative bronchoscopy and CT scan of chest, his symptoms continued for over 4 months. Laboratory investigations were remarkable for slightly elevated serum IgE levels, progressively increasing eosinophils (table 1). Serum α₁ anti-trypsin was normal and aspergillus antibodies were non-reactive. The possibility of carcinoid syndrome was also considered and ruled out with normal urinary 5-hydroxyindoleacetic acid (5-HIAA) level.

Table 1.

Laboratory and spirometry results before during and after the episode of exacerbation of asthma

	Date
	January 2006	January 2007	February 2008	April 2008	May 2008	Fentanyl discontinued June 2008	August 2008
FEV1 (litre)	3.74	3.62			2.12	N/A	3.68
FVC (litre)	4.66	4.54			3.68	N/A	4.40
FEV1/FVC (%)	80	80			58	N/A	83
Serum IgE (<100 KU/litre)				165	174	N/A	146
WBC (4.0–11.0×109/litre)			6.3	9.8	10.3	N/A	5.6
Absolute eosinophil count (0.0–0.5×109/litre)			0.7	2.5	4.29	N/A	0.8

FEV₁, Forced expiratory volume in 1 s; FVC, forced vital capacity; WBC, white blood cell count.

Because of his persistent symptoms and extensive negative work-up, and in view of progressively increasing eosinophil count, the chronological events and medication history was evaluated again in detail and it was noted that the only new medication added prior to the onset of the current exacerbation was fentanyl transdermal patches for low back pain. This time it was decided to stop fentanyl and within 48 h of stopping the fentanyl transdermal patch, his symptoms improved markedly save for a mild tickle in his throat. In all probability, his current exacerbation of asthma was secondary to the fentanyl transdermal patch.

DIFFERENTIAL DIAGNOSIS

Asthma exacerbation.

Carcinoid syndrome.

Eosinophilic syndrome.

Anxiety.

TREATMENT

Withdrawal of the offending agent, a transdermal fentanyl patch in the present case, resulted in complete resolution of symptoms within 48–72 h.

OUTCOME AND FOLLOW-UP

The patient has remained clinically stable since cessation of the transdermal fentanyl patch in June 2008 and the pulmonary function test and eosinophil levels have returned to baseline.

DISCUSSION

All opioids can cause sensitivity reactions, although true allergy is rare. True allergy is IgE-mediated or T cell-mediated. Histamine release from mast cells can cause pseudoallergic reactions that may mimic “true” allergy, and present with flushing, itching, sneezing, hives, sweating, exacerbation of asthma and low blood pressure. Opioids release histamine from mast cells to a variable degree, with codeine, morphine and meperidine having the greatest histamine-releasing capacity, while tramadol, fentanyl and remifentanil do not release histamine and are recommended in pulmonary disease requiring opioid administration.⁶

Fentanyl, a phenylpiperidine derivative, is a semisynthetic opioid. Its extreme lipophilicity facilitates its absorption through multiple routes and a transdermal preparation is now used commonly in the management of chronic pain because of its ease of administration and lower frequency of associated complications. Although most opioids suppress cough, fentanyl may paradoxically induce cough.⁷ Rarely, anaphylaxis⁸ and bronchospasm⁹ can occur. Opioids including transdermal fentanyl should be avoided in acute or severe asthma¹⁰ and should be considered in episode(s) of persistent exacerbation. Testing for IgE to specific opioids may be helpful in diagnosis but not readily available. Elevated total IgE and tryptase levels can occur in allergic states but are non-specific and may occur in anaphylactoid states and a normal level does not exclude allergy.¹¹

This case further illustrates the importance of a basic skill: history, and re-evaluation of a thorough history including medication history, is important at times in solving unrelenting cases such as this.

LEARNING POINTS

• Opioids, especially transdermal preparations, should be considered in patients with persistent symptoms of exacerbation of asthma.

• A thorough history, including a detailed medication history, is important at times in resolving complex cases such as in the present case.

• Patients may bring medications in the form of pills etc. on visiting their doctor, and often the medications that patients take at irregular intervals (not daily) may not be recalled by the patient at their initial visit.