The Hospice Clinician Blog

In hospice, opioids are the most commonly prescribed medications. Nearly every patient ends up needing an opioid at some point in their hospice journey. So what do we do when a patient tells us they are “allergic” to an opioid or to several opioids? Does this mean that all opioids must be avoided?

Fortunately, this is rarely the case. True IgE-mediated opioid allergies are relatively uncommon. In fact, published data suggest that as many as 9 out of 10 patients labeled with an opioid allergy do not have a true allergy. So the first step is to understand exactly what the patient means when they say “allergy.”

Some patients say they are allergic to an opioid when what they have really experienced is not a true allergic reaction but a normal and expected opioid side effect, such as nausea/vomiting, somnolence, confusion or euphoria. These patients may benefit from education regarding opioid side effects—what side effects to expect and how long they will last. Remind patients that tolerance develops to all side effects, except constipation, within about a week. Consider medications to prevent and/or treat troublesome side effects, such as antiemetics for N/V or stimulant laxatives for constipation.

Other patients experience the symptoms of opioid-induced histamine release (a known pharmacologic effect of opioids) and think this “pseudoallergy” is a true allergy. The symptoms of a pseudoallergy can closely resemble those of a true allergy, so a detailed history is necessary to differentiate between the two.

For patients that have experienced a pseudoallergy, opioids can still be used. But choose a more potent opioid (like oxycodone, hydromorphone or fentanyl), because the more potent the opioid, the lower the likelihood of histamine release. Avoid codeine and morphine if possible. Also, consider adding an antihistamine, such as diphenhydramine.

For patients with a true allergy, opioids can still be used, but with caution and close monitoring. Choose an opioid in a different chemical class from the one to which the patient is allergic, as follows:

In many hospice patients, a detailed history is not possible. The patient may be unable to communicate, or may not remember the details of the drug reaction they experienced. In this case, you have to rely on your clinical judgment, weighing the risk of an adverse reaction against potentially compromised pain management.

Please post your comments, questions, or experiences below.

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Introduction to Opioid Induced Pain in Hospice Patients

Howard Hughes, the famous aviation pioneer, film-maker, and billionaire business- man became notorious in his later years for bizarre behaviors that were supposedly related to his addiction to opioids that he used for chronic intractable pain following a serious airplane crash decades earlier. It has been reported that he refused to cut his hair, trim his nails or brush his teeth for years. According to a recent book by Forest Tennant, MD; Howard Hughes & Pseudoaddiction (A brief medical tutorial on a saga of intractable pain) Mr. Hughes' avoidance behaviors were probably related to the severe pain that he experienced from performing these daily activities. The author suggests that he suffered from opioid induced allodynia.

Opioids have been implicated as a possible cause of paradoxical, exaggerated pain responses including allodynia and hyperalgesia. Allodynia is a significant painful response to a stimulus that is normally not painful such as light touch. Hyperalgesia is hypersensitive severe pain response to a stimulus that would normally produce only a very mild pain response. These conditions have been described as opioid induced neurotoxicity, a term that has also encompassed symptoms of myoclonus, seizures, and delirium associated with opioid use.

Hughes died in 1976. In his time these conditions were not recognized as possible opioid induced neurotoxicity, however, in the past several years more reports of the neuroexcitatory side effects of opioids have surfaced as health care providers have become more aggressive at pain management with opioids. Awareness of this unusual phenomenon has increased with the increasing use of opioids for chronic severe pain. These conditions are characterized by generalized, non-specific pain in patients who are receiving rapidly increasing doses of opioids, such as hospice patients. The pain will worsen despite increasing doses of the opioid drug. One of the hallmarks is that the pain becomes more diffuse, with a non-specific location, spreading well beyond the pre-existing sites of pain for which drug therapy was initiated. The patient's pain presentation changes to "pain all over" that doesn't make sense in terms of the underlying disease. The increase in pain is unexplained by increased cancer progression. Allodynia and hyperalgesia have been associated with other neurological symptoms such as myoclonus, seizures, and delirium although hypersensitive pain responses to opioids may occur without these additional symptoms.

Possible Mechanisms

There have been a number of possible mechanisms proposed as to how opioids may cause this paradoxical response. One important proposed mechanism is central nervous system sensitization due to opioid activation of the N-methyl-D-aspartate (NMDA) receptors and activation of intracellular messenger protein kinase C. These two changes result in increased excitability of the nerve cells. Another potential mechanism involves neuronal circuits in the brainstem where opioids may activate pathways that amplify pain signals at the level of the spinal cord.

The accumulation of specific opioid toxic metabolites has also been linked to these conditions. Evidence suggests that both morphine and hydromorphone have active metabolites that are responsible for allodynia and hyperalgesia (morphine-3-glucuronide and hydromorphone-3-glucuronide). Both of these active metabolites are eliminated by the kidneys and usually do not accumulate to produce toxicity, however, in the presence of renal impairment, or rapidly escalating high doses, the metabolites can accumulate and result in allodynia and hyperalgesia. Morphine and hydromorphone induced hyperalgesia is often accompanied by myoclonus, seizures, and/or delirium.

Management of Opioid Induced Pain in Hospice Patients

Although it may seem to be counterintuitive in the face of increasing severe pain, the appropriate intervention in the management of suspected opioid related hyperalgesia and allodynia is to reduce or discontinue the current opioid. Rotation to another opioid with less risk of neurotoxic effects is often an effective remedy. Methadone or fentanyl are appropriate choices for hospice patients who exhibit opioid induced pain on morphine or hydromorphone. Methadone and fentanyl do not have any active metabolites that can accumulate and contribute to neurotoxicity.

Methadone oral is much more cost-effective than the fentanyl patch since oral methadone is priced at approximately one-20th of the cost of an equivalent dose of the patch. Other interventions may include adding a non-opioid adjuvant analgesic medication such as dexamethasone (Decadron), gabapentin (Neurontin), or nortriptyline (Pamelor). Benzodiazepines such as lorazepam (Ativan) or midazolam (Versed) may be helpful in managing myoclonus or muscle rigidity which may accompany opioid induced pain.

Conclusion

The problem of opioid induced allodynia and hyperalgesia is difficult to recognize and interpret, especially in hospice patients. There are no estimates as to the frequency with which opioid induced allodynia or hyperalgesia occurs. It still may be a relatively rare side-effect; however, as hospice and health care providers aggressively manage severe chronic pain with strong opioids we will see an increase in the number of these cases. Any opioid may lead to a paradoxical increase in pain, although the majority of reports are due to morphine and hydromorphone.

Opioid induced pain should be considered in any hospice patient that exhibits increasing pain that does not respond to increasing doses of opioid, especially when the pain complaints become more diffuse, with a non-specific location, spreading well beyond the pre-existing sites of pain for which drug therapy was initiated. Hyperalgesia should be suspected whenever there is need for rapid escalation of opioid doses that is unexplained by disease progression. Opioid dose reduction or rotation to methadone or fentanyl should be considered as the primary method for management for hospice patients.

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Hospice patients may report allergies to opioids, but often these are pseudoallergies consisting of symptoms of itching, flushing and sweating. Pseudoallergy type reactions are relatively common.

True allergy to opioids is rare. (1) Pseudoallergy is caused by release of histamine from the mast cells in the skin, a non-immunologic event. (2) True allergy is believed to be IgE mediated or T-cell mediated. (3) If the reaction is only flushing, itching, or sweating the opioid can often be continued with the addition of an antihistamine or dose reduction. (4) If the true nature of the reaction to an opioid is not clarified, the hospice patient may be incorrectly "labeled" as allergic to opioids and opioid drugs may be withheld unnecessarily.

If the reaction consists of hives, increased heart rate, severe hypotension, or bronchospasm the patient should be assumed to be exhibiting a true allergic reaction and the clinician will need to decide which, if any, opioid is safe for the hospice patient.

Codeine, Morphine, and Meperidine are associated with the most allergictype reactions. (1) It has been suggested that hospice patients allergic to one opioid are less likely to react to an opioid in a different structural class.

It is reasonable to consider rotating from an opioid from one class to one from another distinct class in some situations. The 3 main structural classes are as follows:

• Morphine group: morphine, codeine hydrocodone, oxycodone, oxymorphone, hydromorphone, levorphanol

• Diphenylheptanes: methadone, propoxyphene

• Phenylpiperidines: fentanyl, meperidine

Some patients may experience localized itching and redness underneath the Fentanyl patch. Patch site rotation is very important to reduce this risk. This reaction can be managed by topical application of a steroid, such as triamcinolone spray prior to application of the patch.

Although many hospice patients may report a history of allergy to opioids, most have only experienced a side effect . Proper selection of an opioid medication based upon past history can result in significantly improved outcomes in pain management for the hospice patient.

(1) J Oncol Pharm Practice 2004;10: 177-82 (2) Immunol Allergy Clin North Am 1991;111: 635-44 (3) Anesthesiology 1989; 71: 489-94 (4) Applied Therapeutics: The Clinical Use of Drugs 8th ed. 2005

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