Acute Urticaria: This is the most common cause of sudden onset itching and hives. It can be triggered by allergic reactions to foods, medications, or infections. The fact that symptoms are not better with Benadryl (diphenhydramine) suggests a possible severe reaction or a different underlying cause, but acute urticaria remains a top consideration due to its prevalence.

Allergic Reaction to a Medication: Given that the symptoms are not relieved by Benadryl, it's possible the patient is experiencing an allergic reaction to a different medication, which could include antibiotics, NSAIDs, or other common drugs.
Food Allergy: A sudden onset of itching and hives could be indicative of a food allergy, especially if the patient has recently consumed a new or known allergenic food.
Insect Sting or Bite: Reactions to insect stings or bites can cause widespread itching and hives, and may not respond to initial doses of antihistamines like Benadryl.

Anaphylaxis: Although anaphylaxis typically presents with additional symptoms such as swelling, difficulty breathing, and a drop in blood pressure, it is crucial not to miss this diagnosis due to its potential for fatal outcomes. Early signs can sometimes be subtle, and the lack of response to Benadryl could indicate a severe, life-threatening reaction.
Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN): These are severe skin conditions usually triggered by medications. They can start with symptoms similar to urticaria but progress to blistering and peeling of the skin. Early recognition is critical for management and preventing severe outcomes.
Mastocytosis: A condition characterized by the accumulation of mast cells in one or more organs. It can cause episodes of severe itching, hives, and other systemic symptoms. While less common, it's a diagnosis that should not be missed due to its potential for severe episodes and the need for specific management.

Autoimmune Urticaria: This is a rare condition where the immune system produces antibodies against the body's own tissues, leading to chronic or recurrent urticaria. It might not respond well to conventional antihistamine treatment.
Urticarial Vasculitis: An inflammation of the blood vessels that can cause urticaria-like symptoms. It's a rare condition that might require more aggressive treatment, including corticosteroids or immunosuppressants.
Erythema Multiforme: A skin condition characterized by target lesions, which can sometimes present with itching and hives. It's often triggered by infections or medications and can be severe in its major form, Stevens-Johnson Syndrome.