Paracetamol allergy

Paracetamol allergy is a rare but serious condition that can lead to immediate hypersensitivity including urticaria, angioedema, rhinoconjunctivitis, cough, abdominal pain and anaphylaxis. Patients may present with various combinations of symptoms such as urticaria, swelling of the face and hands, erythema (cutaneous manifestations in 94% of cases), difficulty breathing (including laryngeal oedema ), rhinoconjunctivitis, cough, abdominal pain and anaphylaxis. Paracetamol can cause allergic reactions both due to its pharmacological effects of cyclooxygenase-1 inhibition and due to a rarer selective allergy to paracetamol itself. In some cases, reactions may be due to excipients present in the formula such as mannitol rather than the active substance (paracetamol).

Clinical manifestations may include:

• Urticaria and angioedema, especially on the face and hands.
• Erythema and other skin manifestations.
• Difficulty breathing, including swelling of the larynx.
• Rhinoconjunctivitis, cough and abdominal pain.
• Anaphylaxis in more severe cases.

Diagnosis of paracetamol allergy requires specialist consultation and supervised oral challenge. Some studies suggest the possibility of specific IgE, which may be the mechanism underlying paracetamol hypersensitivity. Importantly, negative skin tests do not exclude paracetamol hypersensitivity, suggesting the possibility of leukotriene mediation. However, three quarters of paracetamol-allergic patients tolerate NSAIDs, suggesting an alternative mechanism.

Treatment of paracetamol allergy involves complete avoidance of paracetamol and any preparations containing it. Patients should be made aware of the paracetamol content of combination products and of the alternative pain relief options available. In cases of confirmed paracetamol hypersensitivity, patient education to avoid any formulations containing paracetamol and explanation of the alternatives available is important.

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Causes paracetamol allergy

Paracetamol allergy, although rare, can be associated with several mechanisms that lead to different types of hypersensitivity. Here are the main causes and mechanisms underlying paracetamol allergy:

1. Immunological mechanisms:

• Specific IgE-mediated reactions: In some cases, allergic reactions to paracetamol may be associated with the production of specific IgE antibodies that recognize and bind to paracetamol, causing the release of inflammatory mediators from mast cells and basophils.
• Cell-mediated reactions: These reactions may involve the recruitment of T lymphocytes that react to paracetamol or its metabolites, resulting in late cutaneous reactions or other forms of hypersensitivity.

2. Non-immunological mechanisms:

• Pharmacological intolerance: In some cases, reactions to paracetamol may not be related to the immune system but are due to the pharmacological effects of the substance itself or its effects on metabolic pathways, such as cyclooxygenase inhibition.
• Excipients: Allergic reactions may not be caused by paracetamol itself, but by excipients present in the dosage form, such as mannitol.

3. Idiosyncrasy:

• Metabolic idiosyncrasy: Rare hypersensitivity reactions may be due to the unique metabolic patterns of individuals, resulting in the formation of immunogenic metabolites that cause allergic reactions.

4. Cross reactions:

• In some cases, paracetamol allergy may be associated with cross-reactivity with other drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), in patients with aspirin-sensitive asthma or NSAID-excerpted respiratory disease (NERD).

Confirmation of a diagnosis of paracetamol allergy requires a thorough history, possibly skin testing, oral challenge trials under the supervision of an allergist and, in rare cases, specific laboratory tests to determine the presence of specific IgE antibodies.

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Pathogenesis

The pathogenesis of paracetamol allergy is not fully understood and may involve different mechanisms. One hypothesis is that paracetamol hypersensitivity may be due to the pharmacological effects of cyclooxygenase-1 (COX-1) inhibition or, less commonly, to selective allergy to paracetamol itself ( Thompson, Bundell, & Lucas, 2019 ). A study by Rutkowski and colleagues (2012) supported that specific IgE may be the mechanism underlying paracetamol hypersensitivity, as 18.8% of patients in their series had specific IgE. In 81.2% of cases, negative skin tests did not exclude paracetamol hypersensitivity, suggesting a possible involvement of leukotrienes in the pathogenesis ( Rutkowski, Nasser, & Ewan, 2012 ).

It has also been suggested that paracetamol hypersensitivity may be associated with non-immunological mechanisms such as direct histamine release from mast cells and basophils, which may be one of the indirect mechanisms involved in allergic reactions to drugs (Bachmeyer et al., 2002).

It has also been hypothesized that some patients with multiple drug allergies may have circulating factors in their blood that trigger histamine release, which may represent a non-specific mechanism underlying hypersensitivity to drugs including paracetamol ( Asero et al., 2003 ).

Overall, hypersensitivity to paracetamol can be mediated through both specific IgE and alternative mechanisms, including leukotrienes and direct histamine release, which highlights the complexity and multifactorial nature of this type of allergic reaction.

Symptoms paracetamol allergy

The most commonly reported symptoms include urticaria, angioedema (face, hands), erythema (cutaneous manifestations in 94% of patients), dyspnea (including laryngeal edema), rhinoconjunctivitis, cough, abdominal pain, and anaphylaxis (Rutkowski, Nasser, & Ewan, 2012). Paracetamol-induced anaphylactic shock has been reported and documented, including cases where skin tests were negative but oral challenge with the drug caused generalized urticaria associated with increased blood histamine levels (Diem & Grilliat, 2004).

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Allergy to paracetamol in a child

Paracetamol allergy in children can present in a variety of ways, from skin reactions to respiratory symptoms, and the severity of these reactions can vary considerably. The incidence of paracetamol allergy is relatively rare, but when it does occur, it can include symptoms such as urticaria, angioedema, dyspnoea and, rarely, more serious hypersensitivity reactions such as anaphylaxis. Cases of allergic and non-allergic hypersensitivity to paracetamol have been described in studies, often with cross-reactivity with non-steroidal anti-inflammatory drugs (NSAIDs) in some patients. In a study of 25 children with suspected paracetamol hypersensitivity, only one child was diagnosed based on the clinical history, indicating the rarity but potential seriousness of such reactions. This highlights the importance of careful consideration and diagnosis when paracetamol hypersensitivity is suspected in children, with the need for alternative pain management strategies if confirmed (Davis & Mikita, 2006), (Kidon et al., 2007).

In addition, a thorough understanding of paracetamol use, including its dosage, routes of administration, and potential toxicity, is critical for parents and caregivers. A cross-sectional study from Palestine highlighted a significant lack of knowledge among parents regarding paracetamol dosage, routes of administration, and its potential toxicity in children. This study highlighted the need for educational efforts to improve parental understanding and awareness of the safe use of paracetamol in children (Daifallah et al., 2021).

In conclusion, although paracetamol is widely used and generally considered safe for children, there is a potential for allergic reactions and hypersensitivity in rare cases. Healthcare professionals should provide guidance and education to parents and carers on the appropriate use of paracetamol and on recognising and managing any adverse reactions.

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Complications and consequences

Paracetamol allergy can lead to various complications and consequences, ranging from mild to potentially life-threatening conditions. Here are the main complications and consequences that patients may face:

Immediate hypersensitivity reactions:

• Anaphylaxis: This is the most serious and potentially life-threatening complication, characterized by a rapid drop in blood pressure, swelling of the larynx, difficulty breathing, tachycardia and may require immediate medical attention.
• Angioedema: Swelling of the fatty tissue under the skin, especially in the face, lips, and around the eyes, which can be dangerous if it causes difficulty breathing.

Skin reactions:

• Hives (urticaria): This is an itchy rash on the skin that may appear and disappear on different parts of the body.
• Fixed drug erythema: The appearance of one or more red spots on the skin that return to the same location when the drug is re-administered.

Respiratory complications:

• Bronchospasm: Narrowing of the airways causing difficulty breathing, wheezing, coughing, especially in patients with asthma or chronic respiratory diseases.

Other complications:

• Stevens-Johnson syndrome and toxic epidermal necrolysis: Rare but severe reactions involving the skin and mucous membranes can result in significant skin peeling, infection, and even death.
• Hematologic disorders: Including thrombocytopenia (low platelet count), anemia, and other blood disorders.
• Hepatotoxicity: Although more often associated with paracetamol overdose, allergic reactions can also contribute to liver damage.

Impact on quality of life:

• Limiting drug choices: The need to avoid paracetamol may limit treatment options for pain and fever, particularly in patients with an NSAID allergy.
• Psychological stress: Anxiety and fear of possible allergic reactions can negatively impact the psychological well-being of patients.

To manage these complications and consequences, it is essential to seek medical attention promptly, strictly follow your doctor's recommendations for avoiding the allergen, and have a clear plan of action in case of allergic reactions.

Diagnostics paracetamol allergy

Diagnosis of paracetamol allergy involves several steps and can be complex due to the rarity of the reaction and the ambiguity of clinical manifestations. Here are some key aspects based on scientific research:

1. Clinical features: Patients with suspected paracetamol allergy may present with a variety of symptoms including urticaria, angioedema (face, hands), erythema (cutaneous manifestations in 94% of cases), dyspnoea (including laryngeal oedema), rhinoconjunctivitis, cough, abdominal pain and anaphylaxis (Rutkowski et al., 2012).
2. Mechanism and diagnosis: The mechanism of paracetamol allergy is poorly understood. A study identified clinical features in 32 patients with suspected paracetamol allergy, investigated the mechanism, and reviewed the tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs). In a number of cases, there were positive skin tests and oral provocation tests confirming hypersensitivity (Rutkowski et al., 2012).
3. Specific IgE: Previous reports of paracetamol hypersensitivity described isolated cases of positive skin tests and detection of specific IgE. The study confirmed that specific IgE may be the mechanism underlying paracetamol hypersensitivity, as 18.8% of patients were found to have specific IgE (Rutkowski et al., 2012).
4. Diagnostic tests: Studies have shown that negative skin tests do not exclude paracetamol hypersensitivity, suggesting that it may be mediated by leukotrienes. However, most patients tolerated NSAIDs, suggesting an alternative mechanism. In patients with suspected paracetamol allergy, skin tests should be performed, as well as clinical history and oral provocation tests (Rutkowski et al., 2012).

These data highlight the need for a comprehensive approach to the diagnosis of paracetamol hypersensitivity, including a careful history, skin testing and oral provocation tests to confirm the diagnosis.

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Treatment paracetamol allergy

Treatment of paracetamol allergy, like any other drug allergy, should be aimed at avoiding the allergen, relieving symptoms and preventing severe reactions. Here are the main methods and stages of treatment:

1. Avoidance of the allergen

• The main step is to completely avoid taking paracetamol and drugs containing paracetamol. Patients should carefully read the composition of all medications they take.
• Education – patients should be informed of the need to notify all healthcare professionals (doctors, pharmacists) of their allergy to paracetamol.

2. Relief of symptoms

• Antihistamines (eg, loratadine, cetirizine) may be used to relieve mild allergic reactions such as itching or hives. The adult dosage is usually 10 mg once daily.
• Corticosteroids (eg, prednisolone) may be used for more severe reactions. The dosage depends on the severity of the reaction and is determined by your doctor.
• Adrenaline (epinephrine) is used for emergency treatment of anaphylaxis. Adrenaline auto-injectors (such as EpiPen) should be given to patients with a history of anaphylaxis, and they should carry them with them at all times.

3. Alternative pain therapy

• Alternative analgesics such as ibuprofen or naproxen may be recommended for patients allergic to paracetamol, unless contraindicated. However, these drugs should be used with caution in individuals allergic to NSAIDs.
• For people at risk of allergic reactions to NSAIDs, other types of analgesia may be recommended, such as opioid analgesics in cases of severe pain, but only under strict medical supervision.

4. Allergy Action Plan

• Developing a personalized allergy action plan, including a list of allergens, methods for avoiding exposure to them, medications needed and their dosages, and first aid instructions for anaphylaxis.

It is important to remember

Treatment and medication selection should be done under the supervision of a qualified allergist or other healthcare professional. Epinephrine auto-injectors should be used as directed and the patient should be trained in their use.

If any signs of anaphylaxis occur, seek emergency medical attention immediately.

Prevention

Prevention of paracetamol allergy involves several key strategies to minimise the risk of developing allergic reactions. The main preventive measures are:

Awareness:

• Reading the ingredients of medications: It is important to read the ingredients of all medications carefully to avoid those containing paracetamol, especially if you have a known allergy or predisposition to it.
• Informing healthcare professionals: When visiting a doctor, dentist or going to hospital, you should disclose any known allergies to medications, including paracetamol.

Use paracetamol with caution:

• Avoid frequent use: Regular or frequent use of paracetamol may increase the risk of developing an allergy, so its use should be limited, especially without a doctor's prescription.
• Alternative methods of pain relief: Considering alternative methods of pain relief such as exercise, physiotherapy, using heat or cold may be helpful in reducing reliance on paracetamol.

Medical supervision:

• Consult an allergist: If you suspect an allergy to paracetamol or other medications, consulting an allergist can help identify possible allergens and develop a prevention plan.
• Prevention during pregnancy and breastfeeding: It is especially important to avoid unnecessary use of medications, including paracetamol, during pregnancy and breastfeeding, as this may affect the risk of developing allergic diseases in the baby.

Training and planning:

• Developing an allergy action plan: For people with a known allergy to paracetamol, it is important to have a clear action plan in case of accidental exposure to the allergen, including having adrenaline auto-injectors available to treat anaphylaxis.
• Education and awareness of others: Relatives and loved ones of people with paracetamol allergy should be educated about the condition so that they can provide assistance if needed.

Prevention of paracetamol allergy requires a comprehensive approach and awareness on the part of both the patient and healthcare professionals.