US Pharm. 2006;7:HS-5-HS-9.

There is growing evidence that numerous drug-induced allergies are not mediated by the pathogenic role of allergen-specific immunoglobulin E (IgE). The case for such non–IgE-mediated, or pseudoallergic, reactions is proposed on the basis of the mechanism of mast cell and basophil activation. The pseudoallergic symptoms can resemble those of a true allergy but are caused by histamine release from cutaneous mast cells. Oral and injectable opioids are among the drugs that cause these symptoms, but the symptoms may not be due to a true allergy. Therefore, in patients who show these reactions, it is important to choose a safe alternative drug. Remember that most patients who say they are allergic to an opioid have experienced only a side effect that has been misclassified as an allergy. Published data suggest that as many as nine out of 10 patients labeled with an opioid allergy do not have a true allergy.1 On the other hand, patients who are considered allergic to an opioid present a serious challenge to clinicians because pain is not always controlled with nonopioid alternatives such as NSAIDs. This article briefly discusses the true opioid allergy versus pseudoallergy, opioid side effects, and alternative options to control pain.

Allergy Symptoms
All opioids, particularly the naturally occurring and semisynthetic compounds, cause allergic reactions. Codeine, morphine, and meperidine are the main opioids that cause most allergic-type reactions. Although some of the symptoms resemble those of a true allergy, they are in reality symptoms of pseudoallergies caused by endogenous histamine release from the mast cells, which is also considered a pharmacological effect. These symptoms include flushing, itching, sneezing, hives, sweating, exacerbation of asthma, and low blood pressure, and their occurrence depends on the concentration of opioids in the mast cells. A true allergy to opioids is rare and seems to be IgE mediated or T-cell mediated. Symptoms of a true opioid allergy include hives, maculopapular rash, erythema multiforme, pustular rash, severe hypotension, bronchospasm, and angioedema.1,2

Classification of Opioids
There are three different chemical classes of opioids. They are as follows:
• Phenanthrenes--codeine, hydromorphone, levorphanol, morphine, oxycodone, hydrocodone, and pentazocine.
• Phenylpiperidine--meperidine and fentanyl.
• Phenylheptane--methadone and propoxyphene.
Often, a patient who is allergic to an opioid from one class (e.g., morphine, a phenanthrene) may be treated with an agent from another class (e.g., methadone, a phenylheptane) without cross-sensitivity. Even though the risk of cross-sensitivity is extremely low, patients who exhibit a true allergic reaction to one of the opioid analgesics should be monitored carefully if an agent from another class is substituted. For example, IgE antibodies isolated from a patient allergic to morphine were able to bind to fentanyl. Morphine antibodies have also shown some reactivity with methadone and meperidine.2

Diagnosis of Opioid Allergy
It is important to distinguish between nonallergic and allergic patients. If the nature and cause of the reaction are not clear, the administration of opioids should not be withheld. In the event that the reaction is found to be opioid related, information from the patient's medical history can be used to choose a safer opioid. As an example, if the patient was able to tolerate other opioids, it may give a clue to a new narcotic choice. Other helpful points may be the symptoms, food, and other medications that the patient has taken before the reaction. Review of a patient's medical records and medication profile may be helpful in diagnosis. Normally, elevated total IgE levels during the acute allergic reaction suggest a true allergy, but IgE could also be elevated for reasons unrelated to drug allergy.1,3

Tests for IgE to specific opioids have been developed but are not readily available. Skin testing has been suggested before a structurally unrelated opioid is used in a patient with a serious opioid reaction.4 Yet false-positive results due to pharmacologic histamine release have been documented with codeine, morphine, and meperidine. If the above methods of determining whether a reaction is a true allergic reaction do not produce satisfactory results, the patient should be referred to an allergist or immunologist for further work-up.

Adverse Effects vs. Allergy and Their Management
Patients should always be informed and educated about possible side effects of opioids and monitored for adverse side effects on a regular basis. Some of the most common side effects of opioids are constipation, dry mouth, nausea, vomiting, and mental confusion. Histamine-release reactions are considered both a symptom of pseudoallergy as well as an adverse effect.

The majority of patients taking opioids on a chronic basis will develop constipation, a side effect of all opioids--that is, opioid-receptor–mediated with both central and peripheral mechanisms (decreased gastrointestinal motility). The best course of action is to prescribe a stool softener (psyllium or docusate) and to instruct the patient in the use of a stimulant or enema as needed, at the time of the original opioid prescription. Some patients may require daily, regularly scheduled laxatives or bowel therapy.5 Another very common side effect is dry mouth. Regular sips of water, artificial saliva, or sorbitol-sweetened hard candy (which also counters constipation) may help to relieve dry mouth.

It is reported that in clinical practice, about 30% to 60% of patients receiving opioid therapy will develop nausea and/or vomiting in the beginning but will develop tolerance within five to 10 days. It is important to note that the pain, along with the anxiety associated with it, can cause nausea independent of opioid therapy. It is generally believed that some of the effect may come from stimulation of opioid receptors at the chemoreceptor trigger zone in the medulla. If the effect is receptor-related, equianalgesic doses of different opioids are expected to produce the same amount of nausea. Patients beginning long-term opioid therapy, and especially those with a history of nausea and/or vomiting with opioids, should have access to prophylactic antiemetics. The most-preferred antiemetics are metoclopramide 10 mg or pro­ ­ chlorperazine 10 mg every four to six hours as needed. If nausea is not adequately controlled with predose antiemetics, and the patient does not develop tolerance, an alternative route of administration or analgesic may be necessary.3,6

Opioid Toxicity
There are several symptoms and conditions, such as confusion, agitation, visual defects, vivid dreams or nightmares, and visual and auditory hallucinations, that may be due to opioid toxicity. These symptoms differ from patient to patient and are dependant on the dose of opioids, pain response, rate of dose titration, concomitant medications, and renal and hepatic function. Opioid toxicity can be managed by giving adequate hydration, acutely treating agitation, reducing the dose of the opioid, or changing to a different one.4

Another important issue is pharmacological tolerance, defined as a decline in pain relief with increasing opioid dose. In some cases, it is not clear whether the lack of response to the analgesic is due to the tolerance, disease progression, noncompliance, or inappropriate dosing. In any case, switching to another opioid may provide improved analgesia, although there is no evidence that one opioid is more effective than another.7

Choosing an Analgesic
In patients with history of allergic-type opioid reactions such as flushing, itching, sweating, hives, and/or mild hypotension, the opioid dose should be reduced and an antihistamine administered simultaneously. The pseudoallergic reactions appear to be a function of opioid dose and potency; therefore, a higher-potency opioid may be helpful, but it needs to be given at a lower dose and rate. In the event that an opioid is necessary, an opioid in a different structural class can be selected; however, the patient needs to be monitored closely. 3

If a patient is labeled as having an allergy to codeine or morphine, clinicians may want to use a synthetic opioid such as meperidine or fentanyl. These drugs have disadvantages; meperidine is short acting and is associated with central nervous system (CNS) adverse effects, such as seizures, even in patients with good renal function. Fentanyl is a potent alternative to morphine, but it is not available as a tablet or capsule, and some patients show a reaction under the fentanyl patch. Both methadone and levorphanol must be dosed cautiously. Their long half-lives can cause drug accumulation and CNS and respiratory depression with repeated dosing. Tramadol is not an option for patients allergic to any opioid; it is contraindicated, according to the prescribing information. Propoxyphene and codeine are not recommended, due to poor efficacy. Pentazocine should be avoided, due to psychiatric side effects (e.g., dysphoria).1,3

Most of the time, a substitute for morphine or another opioid is unnecessary because the patient has experienced a side effect rather than an allergic reaction. For patients with a history of allergic-type reaction, options include a nonopioid or a carefully chosen opioid, but risks and benefits must be considered. The mild to moderate pain may be best alleviated by acetaminophen or an NSAID. Many NSAIDs, opioids, and adjuvant analgesics require dosage adjustment in the elderly, in whom renal or hepatic function may be compromised.3,7

Opioid Dosing Considerations
1. As doses are increased, the respiratory center may become less sensitive to carbon dioxide, resulting in respiratory depression. A decrease in respiratory rate is often preceded by severesedation. The risk of respiratorydepression isincreased by excessive doses (i.e., doses greater than those needed to relieve pain) or doses given when there is no pain.Opioids must be titrated against pain to keep respiratory depression at a minimum. Pure narcotic antagonists (e.g., naloxone, naltrexone) reverse respiratory depression. Sudden, severe sedation often precedes respiratory depression and is a warning sign todecrease the dose or increase the dosing interval.6,7
2.Sedation is very common during the first few days of opioid administration and upon subsequent dose increases, but it often resolves quickly. Sedation is synergized by concomitant use of other medications with CNS-depressanteffects (e.g., antidepressants, anticonvulsants, and skeletal muscle relaxants).
3. Abrupt discontinuation or significant decrease in opioid dosing in all chronic users of opioids will precipitate some degree of withdrawal. Commonsymptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms that may develop include irritability, anxiety, backache, joint pain,weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased respiratory or heart rate.Adequate hydration and nutritional support help make the patient comfortable and decrease morbidity caused by vomiting and dehydration.6

The Pharmacist's Role
Pharmacists have the opportunity to intervene and identify patients with these pseudoallergic or true allergic problems. They can have an important role in ensuring patient access to pain medications, as well as in monitoring for allergies, side effects, and interactions. While dispensing medication, the pharmacist also can collect and evaluate information on pharmacotherapy and consult the patients about their pain medications and the outcome. It is also important that pharmacists know enough about pain management, allergies, pseudoallergies, and side effects to distinguish allergic from nonallergic patients. The pharmacist's knowledge and participation in pain management teams is not only a necessity to enhance patient quality of life but also a resource of drug information for the other members of the medical team.

1. Drugs and Therapy Bulletin at the University of Florida. 2004;18:1-4.
2. Many people think they're allergic to opioids. Pharmacist's Letter/Prescriber's Letter . 2006;22:220-221.
3. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician. 2005;71:913-918.
4. Nasser SM, Ewan PW. Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Clin Exp Allergy. 2001;31:1014-1020.
5. Tripp DM, Brown GR. Pharmacist assessment of drug allergies. Am J Hosp Pharm. 1993;50:95-98.  
6. Otis JA, Fudin J. Use of long-acting opioids for the management of chronic pain. US Pharm. 2005;30(3 suppl):1-14.
7. Crabe ES. Narcotic allergy. P & T. 1996;21:250-252.

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