Hives not responding to antihistamines

Urticaria (hives)

You should also be referred to a dermatologist if you just have chronic urticaria and the symptoms continue, despite treatment.

Chronic urticaria is treated with antihistamines. You may have to take them regularly for as long as your symptoms last.

An increased dose may be recommended if your symptoms don’t respond to treatment. Increasing the dose can often help to control symptoms that previously didn’t respond to treatment. However, this should only be carried out under the instruction of the doctor in charge of your care.

Menthol cream

Menthol cream can be used as an alternative or in addition to antihistamines because it helps to relieve itchiness. Your GP can prescribe this.

Corticosteroid tablets

Occasionally, more serious episodes of urticaria can be treated with short doses of corticosteroid tablets, such as prednisolone. Possible side effects of corticosteroid tablets include:

  • increased appetite and weight gain
  • mood change
  • difficulty sleeping (insomnia)

Long-term use of corticosteroids for chronic urticaria isn’t recommended for the reasons mentioned above.

H2 antihistamines

The type of antihistamines you can get from the pharmacist are known as H1 antihistamines. However, there are several other types of antihistamines, including H2 antihistamines.

H2 antihistamines can sometimes be useful for treating chronic urticaria, because they narrow blood vessels, which can reduce the skin’s redness.

H2 antihistamines can be used as an alternative to H1 antihistamines or in combination with them. Side effects of H2 antihistamines are uncommon, but include:

  • headache
  • diarrhoea
  • dizziness

Don’t drive or use tools or machinery if you feel dizzy after taking a H2 antihistamine.

Leukotriene receptor antagonists

Leukotriene receptor antagonists are a type of medication that can help to reduce redness and swelling of the skin.

They can be a useful long-term alternative to using corticosteroid tablets, because they don’t carry the same risk of causing wide-ranging side effects.

The side effects of leukotriene receptor antagonists are rare and relatively minor. They include headaches and nausea (feeling sick).


In around two-thirds of cases, a powerful medication called ciclosporin has proved effective in treating urticaria.

Ciclosporin works in a similar way to corticosteroids. It suppresses the harmful effects of the immune system and is available in capsule form or as a liquid.

Side effects of ciclosporin include:

  • high blood pressure (hypertension)
  • kidney problems
  • increased levels of blood cholesterol
  • headaches
  • involuntary shaking (tremors)
  • increased vulnerability to infection, particularly chest infections, urinary tract infections (UTIs) and a type of viral infection known as cytomegalovirus

There are also a number of other side effects that can occur when taking ciclosporin, and you should discuss these thoroughly with your doctor before starting.

Side effects, such as high blood pressure and high cholesterol, are a particular cause for concern, because they can increase your risk of heart disease and stroke.

Even if you still respond to treatment, it may be recommended that the medication is withdrawn after a few months.


For urticaria that hasn’t responded to antihistamines, there are newer medications becoming available, such as omalizumab. Omalizumab is given by injection and is thought to reduce a type of antibody that can play a part in urticaria.


There’s some uncertainty over the role of diet in people with long-term urticaria. There are 2 groups of chemicals in foods that may trigger urticaria in some people –vasoactive amines and salicylates.

The Allergy UK website has more information on:

  • vasoactive amines
  • salicylates

Avoiding or cutting down on foods that contain these chemicals may improve your symptoms. You could also keep a food diary to see whether avoiding certain foods helps you.

However, you should talk to a dietitian before restricting your diet. They can make sure you’re not avoiding foods unnecessarily and that your diet is healthy.

Avoiding triggers

If you know what triggers your urticaria or makes it worse, avoiding the trigger may keep your symptoms under control.

Triggers such as alcohol and caffeine can be easily avoided. If you think that a certain medication may be triggering your symptoms, contact the doctor who prescribed it, because alternatives may be available.

Avoiding stress can be more difficult, particularly if your symptoms negatively affect your quality of life.

If you have severe urticaria or urticaria that keeps coming back, you may find that relaxation techniques, such as meditation or hypnosis, reduce your stress levels and the severity of your symptoms.

Treating Chronic Idiopathic Hives

Breaking out in red, itchy hives is especially frustrating when you can’t figure out the cause of the welts. “They appear out of nowhere and can be anywhere on the body,” says Angela Lamb, MD, an assistant professor of dermatology and director of the Westside Mount Sinai Dermatology Faculty Practice in New York.

If you have hives that last longer than six weeks or recur over months or even years, they’re considered chronic. If you can’t identify the cause, they’re labeled chronic idiopathic urticaria (hives).

Medication for Chronic Hives

It’s easier to prevent hives if you know what triggers them and can avoid those culprits. If you can’t identity your triggers, your doctor may recommend one or more of these medications to help relieve symptoms:

Antihistamines. Your first line of defense against chronic hives is longer-acting antihistamines, such as loratadine, fexofenadine, and cetirizine, says Stanley Fineman, MD, of Atlanta Allergy & Asthma, adjunct associate professor in the department of pediatrics, allergy division, at the Emory University School of Medicine, and a past president of the American College of Allergy, Asthma & Immunology.

Your body releases substances called histamines during an allergic reaction. Blood vessels get the signal to dilate, which causes swelling. Antihistamines, available over the counter and by prescription, block that message.

“Antihistamine medications should start helping pretty quickly — within an hour or two,” Dr. Fineman says. But you may need to allow up to two weeks to see if they help overall. Antihistamines don’t have serious side effects, but they may cause drowsiness and can make your mouth dry.

Most people get at least some relief with antihistamines. However, Dr. Lamb says that some individuals may need a combination of antihistamines to control their hives, such as a sedating antihistamine at bedtime and a non-drowsy formula during the day.

If antihistamines don’t help, your doctor might have you add H2 blockers, commonly used to treat heartburn. Histamines not only cause allergic reactions that can lead to hives, but also stimulate cells in the lining of your stomach that produce hydrochloric acid. Available H2 drugs are nizatidine, famotidine, cimetidine, and ranitidine. They’re only effective for hives when used in combination with first-line antihistamines.

Corticosteroids. If you don’t respond to antihistamines, your doctor may recommend corticosteroids, such as prednisone, for chronic hives. These drugs can be taken orally or by injection. Corticosteroids reduce inflammation. Like antihistamines, they should work rather quickly, Fineman says.

While corticosteroids are used to treat severe outbreaks of hives, they aren’t a long-term solution because of their side effects. You should take the lowest possible effective dose for the shortest amount of time because prolonged use of corticosteroids can cause weight gain and high blood pressure. Long-term use can also increase your risk for heart attack, liver cancer, and infections.

Antidepressants. Some tricyclic antidepressants, such as doxepin, have antihistamine effects at low doses. Antidepressants may cause you to be dizzy or drowsy, so you might benefit from taking doxepin at bedtime to help relieve the itch of hives and allow you to sleep. You should see improvement fairly quickly.

Omalizumab. This biologic drug was first created as an asthma treatment, but in 2014 it was also approved for treating chronic hives in people who haven’t responded to antihistamines. An injectable medication, it must be given by a healthcare provider, usually once a month. Omalizumab appears to be safe and effective for chronic hives, according to a study published in March 2013 in the New England Journal of Medicine. You may not see results right away — it may take a few weeks, Fineman says. Serious side effects are rare, but omalizumab can increase your risk for some forms of cancer and infection. There’s also the risk of severe allergic reaction (anaphylaxis) which requires immediate medical treatment with adrenaline (epinephrine).

Leukotriene modifiers. When you come in contact with allergens that can trigger hives, your body releases chemicals that cause inflammation known as leukotrienes. Leukotriene modifiers are medications designed to stop this reaction. They should start working rapidly, but can take up to two weeks. Possible side effects are flu-like symptoms, headache, stomachache, congestion, and nervousness. Leukotrienes are best used in combination with antihistamines.

Immunosuppressants. Hives can be an immune response, so suppressing your immune system with a drug like cyclosporine can help prevent them. These powerful medications should work fairly rapidly, Fineman says. Possible side effects include headache, nausea, and increased risk for infection.

Treating Chronic Hives Should Be Individualized

Medications should make your hives go away and stay away. “If you get better, you know your treatment is working,” Fineman says.

If you don’t get better, talk to your doctor about trying a different medication or combination of medications, Lamb says. Allergy testing is also important to try to determine the cause of your hives, she says. Chronic hives can be associated underlying health condition such as thyroid issues, hormonal problems, and cancer in rare cases.

“Every person is different,” Fineman says. “Your treatment should be individualized to how you respond.”


What is histamine?

Histamine is a vasoactive chemical. This means it has an effect on small blood vessels, resulting in dilated capillaries (redness), and leakage of protein-rich fluid into surrounding skin (swelling). Histamine affects nearby nerves resulting in itching. Histamine is stored in granules within mast cells together with other vasoactive chemicals.

Histamine release occurs in the following skin conditions:

  • Insect bites
  • Urticaria (hives), angioedema and anaphylaxis
  • Dermographism
  • Scombroid fish poisoning
  • Urticaria pigmentosa.

What are antihistamines?

Antihistamines are medications that counteract the effect of the natural chemical histamine.

What are antihistamines used for?

Antihistamines are used to reduce symptoms due to type 1 allergic diseases (such as anaphylaxis) and other conditions mediated by histamine, such as urticaria. They do not always result in complete control because they do not counteract the other chemicals that may be responsible for the symptoms.

There are at least two kinds of histamine receptors, hence antihistamines are classified as H1 and H2 antagonists. Antihistamines used in dermatology are mainly H1 antagonists.

As well as tablets, antihistamines are available as injections, elixirs, and creams.

  • An antihistamine injection can be given in case of severe allergic reaction (although in such cases, adrenaline (epinephrine) may be more appropriate and can be life-saving).
  • Topical preparations (ointments and creams) are often applied to insect bites but are not very effective as the antihistamine chemical does not penetrate the skin well.

As the older type of antihistamines result in relaxation and help to induce sleep, they may be prescribed in other itchy skin diseases such as eczema. They are not thought to be addictive but cause sedation, respiratory depression and cognitive impairment.

Other uses of antihistamines

Antihistamines are also used for:

  • Sedation, for example before an operation
  • Reduce nasal secretions in hay fever or a cold
  • Cough suppressant
  • Counteract motion sickness
  • Increase appetite in those who are unwell.

Conventional antihistamines

Conventional or ‘sedating’ H1 antihistamines are obtainable in New Zealand without prescription. In December 2018 they include:

Short-acting alkylamines

  • Pheniramine (as eye drops for allergic conjunctivitis)
  • Chlorpheniramine maleate /chlorphenamine (Histafen™; and several combination products marketed for upper respiratory tract infections)
  • Dexchlorpheniramine maleate (Polaramine™).

Longer-acting phenothiazines (these can help reduce nausea but can be quite sedating)

  • Promethazine (Phenergan™, Allersoothe™)
  • Trimeprazine or alimemazine (Vallergan™).


  • Diphenhydramine (Unisom Sleepgels™; in combination Benadryl™ for a cough, Panadol Night Caplet™ and others)
  • Doxylamine (Dozile™)

Propylamine derivatives

  • Triprolidine, available in combination (Actifed™, Codral™ Daytime/Nighttime Tablets)


  • Cyclizine, meclozine (Marzine™), often used for travel sickness.


  • Azatadine (Zadine™)
  • Hydroxyzine (Serecid™)
  • Cyproheptadine (Periactin™), which also has antiserotonin effects (useful for a migraine and to increase appetite).

In New Zealand, label statements indicate that sedating antihistamines should not be used in children under the age of 2 years for any reason; they should not be used in children under 6 years for a cough and cold symptoms, and they should not be used for insomnia in children under the age of 12 years. Side effects might be greater in older patients. At any age, the manufacturer’s recommended dose should not be exceeded without medical advice.

Side effects are anticholinergic (antimuscarinic) and include:

  • Drowsiness and slowed reaction times affecting the performance of skilled tasks
  • Dry mouth, blurring of vision, difficulty passing urine and impotence (antimuscarinic effects)
  • Paradoxical stimulant effect (wakefulness and even agitation)
  • Cardiovascular side effects such as irregular heartbeat in higher doses
  • Cognitive impairment and possibly, dementia.

Alcohol in combination with antihistamines could result in excessive and potentially dangerous drowsiness. Care should be taken when combining with other sedative or anticholinergic drugs and when driving, flying or diving underwater.

Because they are broken down by the liver, those with liver disease are best to take a reduced dose as there will be excessive levels circulating in the bloodstream.

In general, all drugs are best avoided in pregnancy, but there is no data to suggest that antihistamines are harmful to the mother or fetus so they are sometimes prescribed for severe urticaria in pregnant women. If a mother is breastfeeding, antihistamines may reduce milk production and could result in drowsiness of the infant, so are best avoided.

Antihistamine creams

  • Mepyramine (Antisan™ cream), an ethylenediamine.

Unfortunately, antihistamine creams can occasionally cause contact allergic dermatitis so they should not be applied to large areas, and should be discontinued if they result in a rash. They should be avoided on broken skin.

Non-sedating antihistamines

Non-sedating antihistamines are much less likely to cause drowsiness and anticholinergic effects but can do so in susceptible individuals. The dose should be reduced in renal impairment and in older people.

Those available in New Zealand (December 2018) are:

Non-sedating antihistamines include rupatidine, which is similar to loratadine. It is not yet available in New Zealand (December 2018).

Terfenadine (Teldane™) and astemizole (Hismanal™) have been withdrawn from the New Zealand market. These drugs may result in electrical disturbances in the heart resulting in palpitations and rarely sudden death when taken at the same time as the following medicines:

  • Erythromycin (ERA™, EES™ )
  • Ketoconazole (Nizoral™)
  • Itraconazole (Sporanox™)
  • Ciclosporin (Neoral™).

H2-receptor antagonists

The second type of histamine receptor (H2) is found in the stomach and skin. H2 blockers were developed to reduce stomach acid secretion and proved useful for patients with peptic ulcers. H2 blockers have been used for some patients with urticaria but are no longer recommended for this indication.

H2 blockers available in New Zealand include:

  • Cimetidine
  • Ranitidine (Zantac™, Peptisoothe™)
  • Famotidine (Pepzan™).

Side effects of H2 blockers are uncommon but include:

  • Gastrointestinal upset (diarrhoea)
  • Hair thinning
  • Gynaecomastia (breast enlargement in males)
  • Confusion, psychosis and possibly dementia due to weak antimuscarinic effects
  • Reversible impotence
  • Blood count, liver, kidney, pancreatic disturbance (very rare).

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

There Is New Hope For Patients With Chronic Hives

By David J. Resnick, MD FAAAI | Allergy/Immunology

What are hives or urticaria?
Hives is a condition that affects an estimated 20 percent of the population at one time or another in their lives. Hives is a rash that causes itching, followed by swollen and red welts. The itching may be mild or severe. The medical term for hives is urticaria. Hives may last for a few minutes, sometimes several hours, and even several weeks or months.

Hives are broken down to two types, acute and chronic. Acute hives last for six weeks or less. Chronic hives last more than six weeks. Most laypeople believe acute hives is mainly triggered by foods. The reality is that the most common cause of acute hives is an infection. After infections, foods and medications are the next most likely culprits.

When dealing with chronic hives, the cause will not be identified despite testing in most cases. This is called idiopathic hives. Forty percent of patients have antibodies (proteins) that attack the mast cell (allergy cell). This triggers chemicals such as histamine to be released which causes the hives and itching. It is also rare for a food to cause chronic hives. In most cases of chronic urticaria, the hives will gradually disappear over time.

What medications treat hives?
There are many different antihistamines that are used to treat hives. Some cause drowsiness, more than others. Over the counter antihistamines such as loratadine (Claritin), fexofenadine (Allegra), levocetirizine, (Xyzal) and cetirizine (Zyrtec) are less likely to cause drowsiness than Benadryl. Whatever is used does not permanently make the hives disappear. When the medications are discontinued the hives can return.

Many chronic hive patients fail routine therapy and then go onto using fancier medications such as prednisone and cyclosporine. These medications can work, but can have significant side effects. Recently the FDA approved Xolair as a treatment for chronic hives. This is an injectable medication that has been used for asthma in the past. The side effect profile is much better than prednisone, and cyclosporine. It works for most patients with chronic hives. This new use for Xolair gives hope to appropriate patients who can go for months or even years without receiving satisfactory itch and hive relief.

If you are a patient with hives, you can make an appointment with one of our allergists to discuss possible therapies.

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