I have a patient who needs neck reconstructive surgery (about a 10 hour procedure) who has clear systemic allergy (angiodema) from all narcotics. Do you think it would be possible to desensitize him in an ICU to morphine or an equivalent prior to the procedure? He will likely be hospitalized for 10-14 days post-op.


Thank you for your inquiry.

I have copied below a response which we recently posted on our website to a similar question. Unfortunately I found nothing in the literature since that time that would change this answer. There is nothing that I have been able to find in the literature that would serve as a protocol for desensitization to morphine. I have not been able to find any cases. Thus, a desensitization protocol could be tried, but there is no precedence to my knowledge that you might use in selecting a protocol or predicting the efficacy of the procedure.

Thank you again for your inquiry and we hope this response is helpful to you.

Question/Answer posted 10/23/13:
Title: Intolerance to morphine and oxycodone
What information do you have on provocation challenge and "desensitization" to a patient who develops hives and itching to morphine? She also develops difficulty breathing to oxycodone. I'm trying to come up with a protocol that I could offer with her next surgery. Do pre-meds work in this scenario?

Thank you for your inquiry.

As you can see from the abstracts copied below, such reactions to opiates are usually due to their direct effect on mast cells. There have been rare reports of IgE-mediated reactions, but their true existence remains debatable. Thus, to my knowledge and according to a literature search, there are no reported “desensitization” procedures.

I have only been able to find one report of a provocative challenge. This was a very brief case report in a journal of pain management. It is available to you via the link copied below. As you can see from looking at this article, however, I do not think the method used would be practical in your situation.

Thus, I am afraid I cannot offer you a published desensitization or graded challenge protocol. Antihistamines have been used successfully in controlling the pruritus associated with opioids (see abstract copied below). Finally, it is thought that fentanyl is less potent as a mast cell degranulating agent and therefore might be less likely to cause your patient to experience the aforementioned symptoms (1).

In summary, unfortunately I could not find an established protocol for desensitization or a graded challenge for your patient. However, antihistamines can be helpful in controlling her symptoms, and fentanyl might be an adequate substitute for morphine or codeine.

Thank you again for your inquiry and we hope this response is helpful to you.

Casale T, et al: Induction of human cutaneous mast cell degranulation by opiates and endogenous opioid peptides: Evidence for opiate and nonopiate receptor participation
Journal of Allergy and Clinical Immunology
Volume 73, Issue 6, June 1984, Pages 775–781
In order to examine the capacity of pharmacologically useful opiates to stimulate human most cell secretion, subjects were skin tested with morphine, codeine, or meperidine hydrochloride. All three agents acted equipotently in eliciting positive immediate skin reactions from all subjects tested. Each agent demonstrated 10 mm of net whealing at 5 to 10 ìg base (16.7 to 40.4 nmol) injected intradermally. The ability to elicit immediate skin test reactions with endogenous opioid peptides was examined with the use of dynorphin, [D-Ala, 2-D-Leu5] enkephalin, beta-endorphin, and morphiceptin. All four compounds induced wheal-and-flare reactions with the order of potency: dynorphin, >beta-endorphin, and >[D-Ala, 2-D-Leu5] enkephalin ≅ morphiceptin at dose ranges of 0.3 to 8.45 nmol. The inhibition of reactivity by hydroxyzine and the demonstration of mast cell degranulation by electron microscopy suggest that the immediate skin responses to opioid stimulation occur as a consequence of mast cell degranulation. Experiments with the opioid receptor antagonist, naloxone, suggest that both opioid and nonopioid receptors may be involved. These results imply that endogenous opioid peptides possibly may play a role in mast cell function and/or degranulation.

Opiate-sensitivity: clinical characteristics and the role of skin prick testing: Clinical & Experimental Allergy
Volume 31, Issue 7, pages 1014–1020, July 2001
Background: The value of skin prick testing in opiate-sensitive individuals is uncertain as opiates cause non-specific weals by direct degranulation of mast cells.
Objective: To define whether skin prick test (SPT) responses to opiates in opiate-sensitive individuals are different to those seen in the normal population and to describe the clinical characteristics of this group of subjects.
Methods: The SPT responses of eight opiate-sensitive subjects to morphine 10 mg/mL, pethidine (meperidine) 50 mg/mL and papaveretum 15.4 mg/mL at four different concentrations (undiluted, 1/10, 1/50 and 1/100) were compared with the responses of 100 (32 atopic) non-opiate-sensitive control subjects. Four of the opiate-sensitive subjects had a clinical history of asthma, rhinitis or urticaria on occupational exposure to morphine. One subject developed urticaria with codeine, one developed urticaria and asthma with morphine and diamorphine and two subjects reacted to intravenous papaveretum with anaphylaxis or urticaria. Five out of the eight cases had opiate sensitivity confirmed by single-blind placebo-controlled oral challenge.
Results: Skin prick tests to all three opiates were not significantly different when the eight opiate-sensitive subjects were compared with either the entire normal control group or the subgroup of 47 definite opiate-tolerant controls that had previously received opiates for clinical indications. Furthermore, there were no significant differences in size of opiate SPT responses between atopic and non-atopic control subjects. In the control subjects, there was a positive correlation in SPT weal size between the three opiates.
Conclusion: Skin prick testing is not useful in the diagnosis of opiate sensitivity and placebo-controlled challenge should be considered.

“Desensitization” of Opioids: A Case Study
(source: J Palliative Medicine)

J Ky Med Assoc. 1991 Jul;89(7):319-21.
Epidural morphine pruritus reduction with hydroxyzine in parturients.
Juneja MM, Ackerman WE 3rd, Bellinger K.
Department of Anesthesiology, Norton Hospital, Louisville, KY 40232-5070.
A majority of patients experience pruritus, nausea and/or emesis following epidural morphine administration post-cesarean section. Naloxone or diphenhydramine are commonly used to treat these side effects. Prevention or reduction in the incidence of side effects of epidural morphine is a clinical goal. The purpose of the study was to observe the efficacy of prophylactic administration of hydroxyzine on the incidence and severity of pruritus following the epidural administration of morphine in 40 patients who requested epidural morphine for postoperative pain relief. Group I (n = 20) received saline, while Group II (n = 20) received 50 mg of hydroxyzine ten minutes after the administration of 5 mg epidural morphine. Both solutions were administered by deep intramuscular injection in the thigh area. The results of this investigation demonstrated that hydroxyzine was efficacious in attenuating the incidence of severe pruritus.

1. “Anaphylaxis during anesthesia, the intraoperative period and postoperative period.” In: Lieberman P, Nicklas R, Oppenheimer J, Kemp S, Lang D, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 Update. Journal of Allergy and Clinical Immunology 2010 (September); 126(3):477-480 e42.

Phil Lieberman, M.D.

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