DISCLAIMER: This article is provided as commentary and discussion, not direct medical advice. Before making any medical decision, consult with your medical provider.
Pharmacists are often consulted for recommendations regarding patient allergies by other health care professionals. One such allergy that is frequently reported by patients is an allergy to an opioid. Sometimes patient-specific reactions are reported in an electronic medical record (EMR), but other times reactions are unknown.
This begs an important question – what can be done for patients who have listed allergies to an opioid? How can a clinician navigate this situation and what do patients need to know?
To address these thoughts, it is important to understand some background about opioids and their associated allergies.
Opioids are usually categorized by both chemical synthesis (the process of creating chemical compounds) and chemical structure.
Morphine’s chemical structure is the basis for most other opioids and it is considered to be a ‘pure opiate’. Pure opiates can be derived directly from the opium poppy plant. Semi-synthetic compounds such as hydrocodone, oxycodone, and hydromorphone are produced by making modifications to pure opiates. Then, there are fully synthetic compounds such as fentanyl, tramadol, and methadone that share less structural similarities compared to pure opiates and semi-synthetics; they are also not produced using naturally-occurring opioids (Table 1).
However, this is not a complete picture. Despite being semi-synthetic, many opioids still share common structures with morphine. A more exact breakdown of opioid structures is demonstrated in Table 2 for reference.1
Table 1. Classes of Opioids by Chemical Synthesis2
| Group 1: Opiates | Group 2: Semi-Synthetic Opioids | Group 3: Synthetic Opioids |
| Morphine Codeine | Hydrocodone Hydromorphone Oxycodone Oxymorphone Buprenorphine Heroin | Fentanyl Methadone Tramadol Tapentadol Meperidine Propoxyphene |
Table 2. Classes of Opioids by Chemical Structure
| Phenanthrenes | Benzomorphans | Phenylpiperidines | Diphenylheptanes | Phenylpropylamines |
| Contains 6-OH Group Morphine Codeine Lacks 6-OH Group* Buprenorphine Butorphanol Hydrocodone Hydromorphone Levorphanol Nalbuphine Oxycodone Oxymorphone | Diphenoxylate | Fentanyl Remifentanil Sufentanil Meperidine | Methadone Propoxyphene | Tramadol Tapentadol |
Unfortunately, the terminology here is inherently technical, but focus less on the terms and more so on the association. Within Table 1, all the semi-synthetic opioids in Group 2 are phenanthrenes that lack a 6-OH group within their chemical structure. When looking at Group 3, all are non-phenanthrene structures. This will be important when discussing trialing opioids in patients with listed allergies.
Pure opiates, semi-synthetics, and synthetics all have side effects common to all opioids (e.g. respiratory depression, sedation, nausea, constipation). However, opioids tend to cause reactions that many patients mistakenly associate as an allergy. Opioids can cause the release of histamine which can cause reddening of the skin, sweating, itching, hives, and/or mild hypotension (low blood pressure). This is commonly called a pseudo-allergy and is most common with pure opiates like morphine and codeine.
Listed reactions such as nausea, constipation, and stomach upset are actually common side effects of opioids; not an allergy. Reactions like hives, redness, itching, and sweating are likely pseudo-allergies. These reactions are not life-threatening and are fairly common.
In fact, allergies to opioids are some of the most commonly listed allergies in hospitalized patients’ medical records – even more so than antibiotics (Table 3). Much like reported penicillin allergies, most of these allergies are not necessarily immune-related and do not require complete avoidance by a medical team.
Table 3. Frequency of Drug Allergy Alerts (Adapted from data published by Topaz M, et al. 2015)3
| Drug Class | Frequency of Drug Allergy Alert |
| Narcotic analgesics (opioids) | 48% |
| Antibiotics | 10% |
| NSAIDs/salicylates | 6% |
| Statins | 2% |
| Other | 34% |
With this in mind, we know that listed allergies to opioids are common. However, for patients with unknown reactions, how common are severe reactions to opioids such as swelling of the lips/tongue or anaphylaxis?
Because humans produce opioid peptide substances (e.g. endorphins and enkephalins) naturally, the likelihood that a patient would have an anaphylactic response to an opioid provided in a medication would seem low. The data appear to validate this sentiment, too.
A review (study) of opioid chart allergies and subsequent opioid administration demonstrated that the rate of an immune-mediated reaction was low (1.6%) and was not significantly different between classes of opioids. 92.5% of patients in the study tolerated receiving another opioid. Of the 461 patients who tolerated administration of an opioid in this review, only one had a possible anaphylactic reaction. This patient continued to receive subsequent doses of the medication that caused the allergic reaction without issue.4
The same study found that out of 789 patients with a listed opioid allergy, only 2 had a possible anaphylactic reaction. In a survey of clinicians regarding opioid allergies (over 50% were pharmacists), 44 out of 54 (81.5%) had not seen an anaphylactic event associated with opioids in their career.4 From what this data shows, the likelihood that a patient would have a severe allergy to an opioid appears very low, and this is from a population of patients a listed history of immune-mediated reactions. In a more general population with non-severe listed allergies, this rate would likely be even lower. This is important to keep in mind when attempting to evaluate listed allergies with unknown reactions and lacking a way to validate or confirm the reaction.
Despite the rarity of a severe allergy, when asked about giving a patient an opioid with an unknown reaction listed, fewer than 15% of clinicians were willing to give the patient the same opioid.4 This is understandable, but this question only addressed giving the same opioid; not a similar alternative. Additionally, it reinforces the fact that gathering a thorough history of the allergy is imperative for making a sound clinical decision.
For most patients, giving an opioid in a different clinical class (pure opiate, semi-synthetic, synthetic) appears to be a safe option (see the data from the retrospective review). For those patients with an unknown reaction, healthcare professionals need to attempt to gather more information about the allergy. This may be done by directly communicating with the patient or by looking through their medical history. Reviewing the medications a patient received during a prior visit to the hospital can be very helpful and provide additional context prior to discussing the allergy with the patient.
For comparison, in patients with listed penicillin allergies, seeing that they received repeated doses of antibiotics similar to penicillin like piperacillin/tazobactam (Zosyn) or ceftriaxone (Rocephin) during prior visits suggests the allergy is non-severe and is tolerable. Many times, the allergy is never corrected despite tolerating therapy. The same thought process applies with opioid allergies. If a patient had a prior surgery or hospitalization of any kind, then they could have received an opioid. If they did, then the potential severity of that allergy likely decreased significantly.
If the allergy cannot be clarified, then the use of another opioid should be considered on a risk/benefit basis and using clinical judgement. But before a healthcare professional chooses an opioid, it is important to consider whether an opioid is even necessary for the treatment of the patient’s pain.
An opioid is not always necessary. Most patients without liver dysfunction should have scheduled or as-needed acetaminophen (Tylenol) provided for baseline pain control. Similarly, for most patients without kidney dysfunction or significant heart disease, non-steroidal anti-inflammatory drugs (NSAIDs) can be added for further pain control. Ibuprofen (Advil) and naproxen (Aleve) are examples of NSAID drugs. There are also compelling indications for non-opioid therapies in certain situations (Table 4). Depending on the exact type of pain, therapies like nerve blocks can also be utilized, but these come with their own risks.
Table 4. Opioid Alternatives by Indication*
| Indication | Non-Opioid Alternative |
| Renal colic (kidney stone pain) | Lidocaine IV Ketorolac IV |
| Site-specific pain (e.g. shoulder, back, rib pain) | Lidocaine patch Trigger-point injections Nerve block |
| Generalized musculoskeletal (muscle) pain | Cyclobenzaprine Methocarbamol Tizanidine |
| Neuropathic pain | Gabapentin Pregabalin Duloxetine Amitriptyline |
| Trigeminal neuralgia | Carbamazepine Lamotrigine |
| Procedural sedation and analgesia | Ketamine |
If an opioid is still required for pain control and opioid alternatives cannot be utilized, then synthetic opioids can be considered. Synthetic opioids theoretically have the lowest risk of cross-reactivity when compared to semi-synthetics and pure opiates and this has been demonstrated in some case studies.1,5
However, these agents do have some unique extra considerations worth evaluating.
Tramadol, a commonly prescribed synthetic opioid, may be an effective agent for treating milder pain but it comes with the risk of serotonin syndrome, and it may not be an ideal drug for patients taking multiple serotonergic medications (medications that affect serotonin levels in the body). Additionally, it should be avoided in patients with a history of seizures or diagnosis of epilepsy.
Methadone is long-acting synthetic opioid and comes with the risk of QT prolongation. Additionally, its long and variable half-life (duration of effect) makes it difficult to quickly titrate to the patient’s acute pain.
FAST FACT: QT prolongation, also called long QT syndrome, is a medical condition that can cause the heart to take longer to rebound after each beat. QT prolongation may lead to dizziness, fainting, heart palpitations (fast/unpredictable heart beat), seizures, etc. If left untreated, it may lead to death in certain cases.
Meperidine, another synthetic opioid, is not recommended for use for greater than 48 hours due to its toxic metabolite, nor-meperidine, and therefore is mostly relegated for the treatment of post-operative shivering (rigors).
In IV formulation, fentanyl is likely best suited for critical care settings where its potency and quick onset of action is beneficial for treating severe acute pain. It is also used as an adjunct therapy option for sedation. As a patch, fentanyl is indicated only for opioid-tolerant individuals (individuals who have been previously given an opioid), which would likely not be the case for a patient with a listed opioid allergy.
If a patient has a non-severe allergy to morphine, then substituting for a semi-synthetic or synthetic opioid would be reasonable. A trial of a semi-synthetic is likely preferred because synthetic agents are typically either 1) very potent or 2) have extended adverse effect profiles. Consider utilizing antihistamines to improve tolerability; but do keep in mind the increased sedation that may occur when co-administering diphenhydramine (Benadryl).
For patients with a severe allergy (e.g. swelling of the lips/tongue, anaphylaxis) to a pure opiate, the conservative route for managing these patients would be to utilize a synthetic opioid. Semi-synthetic opioids should not be used if a patient has a true anaphylactic allergy to morphine. If a semi-synthetic opioid is used, then increased monitoring would be appropriate to quickly respond to any adverse reaction. The risk of cross-reactivity appears low, but it is not zero. If a decision is made to give a semi-synthetic opioid, it is important that the patient’s nurse and other integral members of the patient’s care are aware of the decision.
Summary
Unfortunately, there is limited literature/data available regarding opioid allergies, and treatment decisions made by healthcare professionals are mostly guided by clinical experience and judgement. Despite these limitations, utilizing the data that is available and what is known about the chemical structures of opioids can assist in making an educated decision.
Additionally, for tricky opioid allergy situations, consultation of the pain management service should be considered if one is available. They likely have experience with these situations and since much is guided by clinical judgment their input would be valuable.
Allergies are an important and powerful piece of medical information. They directly impact medical decision-making, regardless of their accuracy. Sometimes this can lead to more expensive care, delays in care, and potentially sub-optimal care. This makes the verification of these allergies a very important process.
When confronted with an opioid allergy, before considering alternative opioids, the patient should be asked about their reaction. This is a key piece of information that is often missed in the collection of allergy information. A conversation should be had regarding the patient and provider’s willingness to retry the medication or a similar one – any medication choice should be a shared decision between the patient and provider whenever possible. As a patient, it is essential to inform a healthcare team everything that is known about a potential opioid allergy so an informed treatment decision can be made from all perspectives. Providers must always weigh the risks and benefits of treatment.
In the case of opioid allergies, it appears that the vast majority of listed allergies are actually just side effects or intolerances to the medication. Rarely is this allergy truly anaphylactic, but this is no reason not to exercise caution for patients with unknown reactions. Extra attention and monitoring may be warranted to ensure no harm is done.
References:
- Li PH, Ue KL, Wagner A, Rutkowski R, Rutkowsi K. Opioid hypersensitivity: predictors of allergy and role of drug provocation testing. J Allergy Clin Immunol Pract. 2017;5(6):1601-6.
- Hayes B. UMEM Educational Pearls – Opioid Allergies and Cross Reactivity. University of Maryland Department of Emergency Medicine. Updated 21 March 2021. Accessed 21 March 2021. Accessible via: https://umem.org/educational_pearls/578/
- Topaz M, Seger DL, Slight SP, et al. Rising drug allergy alert overrides in electronic health records: an observational retrospective study of a decade of experience. J Am Med Inform Assoc. 2016;23(3):601-8.
- Powell MZ, Mueller SW, Reynolds PM. Assessment of opioid cross-reactivity and provider perceptions in hospitalized patients with reported opioid allergies. Ann Pharmacother. 2019;53(11):1111-23.
- Kalangara J, Potru S, Kuruvilla M. Clinical manifestations and diagnostic evaluation of opioid allergy labels – a review. J Pain Palliat Care Pharmacother. 2019;33(3-4):131-140.
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