“If a=b and b=c, then a=c” Euclid (as taught to me by my 10th grade math teacher, Mrs. Greenwald).
Review Article
Eileen Nguyen, Grace Lim, Sarah E Ross. Evaluation of Therapies for Peripheral and Neuraxial Opioid-induced Pruritus based on Molecular and Cellular Discoveries. Anesthesiology; 2021 Aug 1;135(2):350-365. PMID: 3423713
We know that histamine causes itching (a=b) and morphine releases histamine (b=c), ergo (great word isn’t it?), morphine causes itching by releasing histamine, right? Well, yes and no. If you think about it, the opioid that causes the most itching is fentanyl, and it does not cause histamine release. Further, regardless of the opioid (and histamine releasing properties), the route of opioid administration plays an important role in opioid-induced pruritus. Neuraxial (spinal or epidural) morphine administration causes a lot of itching, whereas oral morphine administration much, much less so. IV administration is somewhere in between (PCA causes itching in 10-50% of patients). And for those of you who do acute pain management, you know that itching can be so maddening and so difficult to treat, that it is amongst the most common reasons for switching from one opioid to another or the discontinuation of opioid therapy altogether.(1,2) So, what is the mechanism of opioid induced itching?(3)
This is a great review article that focuses on neuraxial induced pruritus in adult (mostly OB) patients and I’ll review some of the key points. The authors seem to discount opioid receptor mediation in pruritus caused by parenterally administered opioids, especially fentanyl or hydromorphone, yet it is effectively treated by centrally but not peripherally acting opioid antagonists.(3) I realize that their main focus is neuraxial opioids, especially in the OB setting, but I found this a failing in their paper.
Because of the need for brevity in the PAAD, I will limit my discussion to treatment options and have included a figure highlighting where these drugs work and a table with ADULT drug dosing. For those interested in the proposed mechanisms of opioid-induced pruritus, please read this review article and a previous one by Ganesh and Maxwell.(3)
1. Histamine receptor antagonists (e.g., diphenhydramine “Benadryl”) reduce itch primarily by causing patients to fall asleep. Their actual effectiveness as anti-pruritics is very questionable even though most practitioners use them as their first line therapy.
2. Mu opioid antagonists (e.g., naloxone) given at very low doses (0.25-0.1 mcg/kg/HOUR) by continuous infusions are very effective.3,4 Mixed agonist/antagonists (e.g., nalbuphine and butorphanol) are also clinically very effective and work by partially blocking the mu receptor AND by binding to kappa receptors. The advantage of these drugs is that by binding to the kappa receptor they may be better at preserving analgesia than the pure antagonist naloxone. The disadvantage is that they can be very sedating and may cause dysphoria. Both mu opioid antagonists and mixed agonist/antagonists are also effective at treating pruritus from other causes such as uremia, cholestasis, and contact dermatitis.
3. Selective kappa receptor agonists. This class of drugs is only approved for use in Japan. As with all kappa agonists, central sedation is always an issue.
4. Gabapentin is effective for several forms of non-opioid induced pruritus. It is unclear how well it works for opioid induced pruritus. The adult doses studied are very high (1200 mg) and sedating.
5. Emerging therapies include not only the selective kappa agonists discussed above but a peripherally acting kappa drug that may not cause sedation.
References
DiGiusto M, Bhalla T, Martin D, Foerschler D, Jones MJ, Tobias JD: Patient-controlled analgesia in the pediatric population: morphine versus hydromorphone. J Pain Res 2014; 7: 471-5
Cravero JP, Agarwal R, Berde C, Birmingham P, Cote CJ, Galinkin J, Isaac L, Kost-Byerly S, Krodel D, Maxwell L, Voepel-Lewis T, Sethna N, Wilder R: The Society for Pediatric Anesthesia recommendations for the use of opioids in children during the perioperative period. Paediatr Anaesth 2019; 29: 547-571
Ganesh A, Maxwell LG: Pathophysiology and management of opioid-induced pruritus. Drugs. 2007; 67: 2323-2333
Maxwell LG, Kaufmann SC, Bitzer S, Jackson EV, Jr., McGready J, Kost-Byerly S, Kozlowski L, Rothman SK, Yaster M: The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study. Anesth.Analg. 2005; 100: 953-958
Monitto CL, Kost-Byerly S, White E, Lee CK, Rudek MA, Thompson C, Yaster M: The Optimal Dose of Prophylactic Intravenous Naloxone in Ameliorating Opioid-Induced Side Effects in Children Receiving Intravenous Patient-Controlled Analgesia Morphine for Moderate to Severe Pain: A Dose Finding Study. Anesth.Analg. 2011