70 Journal of Pain and Symptom Management
Vol. 17 No. 1 January 1999
Opioid-Induced Itching: Morphine Sulfate and Hydromorphone Hydrochloride Jerald Katcher, MD, and Declan Walsh, MSc, FACP Department of Radiation Oncology (J.K.), Palliative Medicine Program (D.W.), Department of Hematology/Oncology (D.W.), Cleveland Clinic Cancer Center, Cleveland, Ohio; and Harry R. Horvitz Center for Palliative Medicine (D.W.), Cleveland Clinic Foundation, Cleveland, Ohio
Abstract We describe a case of severe morphine-induced itch unrelieved by antihistamines, which responded to a change to hydromorphone. The possible mechanisms of opioid-induced itch are briefly discussed. It is unclear if it is due to histamine release, an opioid-receptor mediated effect, or idiosyncratic drug reaction. J. Pain Symptom Manage 1999;17:70–72. © U.S. Cancer Pain Relief Committee, 1998. Key Words Opioid side effects, itch, morphine, hydromorphone, parenteral opioids
Troublesome opioid side effects may sometimes limit both patient and physician acceptance of these invaluable drugs. The most common side effects of oral morphine during repeated dosing for cancer pain seem to be dry mouth, sedation, and constipation.1 When utilizing alternative routes of opioid administration, epidural hydromorphone or morphine may provide comparable analgesia. Itch with epidural morphine may be troublesome but is apparently reduced with switching to the use of epidural hydromorphone.2 We report a case to illustrate that this phenomenon may also occur when prescribing oral or intravenous morphine and hydromorphone.
A 62-year-old Korean man with locally recurrent transitional cell carcinoma, status post right nephrectomy, chemotherapy (methotrexate, vinblastine, doxorubicin, cisplatin), and radiation therapy (3000 cGy in 10 fractions to the right renal bed), was seen in consultation for pain control. The pain was described as sharp, beltlike around the waist, radiating from the right flank into the right groin, and worsened with increased abdominal pressure. Physical examination was essentially unremarkable. The vertebral column was nontender and the abdomen was soft with mild right upper quadrant tenderness on deep palpation. Computerized tomography of the abdomen was consistent with liver metastases and residual tumor in the right renal bed; magnetic resonance imaging of the entire spine was negative for metastatic disease. At the initial consultation, the analgesic regimen was controlled-release morphine (MS Contin, Purdue Frederick, Norwalk, CT) 15 mg by mouth every 8 hours with 5 mg of liquid morphine (Roxanol, Roxane Laboratories, Co-
A World Health Organization Demonstration Project Address reprint requests to: Declan Walsh, MSC, FACP, FRCPEdin, Director, Harry R. Horvitz Center for Palliative Medicine M76, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Accepted for publication: April 30, 1998. © U.S. Cancer Pain Relief Committee, 1998 Published by Elsevier, New York, New York
0885-3924/99/$–see front matter PII S0885-3924(98)00115-8
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lumbus, OH) by mouth every 4 hours as needed. This regimen provided only partial pain relief. He noted severe generalized itching since starting on oral morphine. This was discomforting enough that it inhibited his willingness to take morphine at all and had required the use of diphenhydramine (Benadryl, Parke-Davis, Morris Plains, NJ) 25 mg by mouth every 4 hours as needed for 1 week. The itch was not relieved by this therapy. He had no prior history of skin disorders, asthma, drug allergies, wheezing, or urticaria. His skin exam was unremarkable— there was no erythema, rash, dermatitis, or urticaria. Routine laboratory studies, including liver and renal function, were unremarkable. There was no eosinophilia. Serum immunoglobulins were significant for a moderate increase in IgA to 567 mg/dl (normal 78–391 mg/dl). The patient was admitted to the hospital due to increasing right flank and groin pain unresponsive to increased doses of oral morphine. His morphine was changed to a continuous intravenous infusion using an oral: parenteral relative milligram potency ratio of 3:1. The dose was aggressively titrated over a 48-hour period, with major improvement in pain control but continued intolerable itch. Empirically, the patient was switched to an equianalgesic3 dose of hydromorphone (Dilaudid, Knoll Pharmaceuticals, Whippany, NJ), specifically 1 mg/hr by continuous infusion. The itch stopped within 24 hours of starting the hydromorphone. The patient described his symptoms as “the difference between heaven and hell.” The hydromorphone was then further adjusted to achieve optimal pain control; it was possible to decrease the hydromorphone dose, perhaps because of decreased patient anxiety with resolution of the itch. Once pain control stabilized, the intravenous hydromorphone dose (0.4 mg/hour) was converted to an oral dose (8 mg every 4 hours and 4 mg every 4 hours as required) using an IV:PO relative milligram potency ratio for hydromorphone of 1:5. The patient was discharged with good pain control and no further itch. Subsequent repeated outpatient visits confirmed this finding.
Discussion The etiology of opioid-induced itching is unknown but may be due to either a direct cen-
tral effect4 or to histamine release.5 Morphine causes dilatation of cutaneous blood vessels; the skin of the face, neck, and upper thorax may become flushed. These changes may be due to the release of histamine and cause the sweating and itch that occasionally follow systemic morphine administration.6 In this case, the itching was unresponsive to antihistamines and skin examination was unremarkable. As IgE levels were normal and there was no eosinophilia, the mechanism of morphine-induced itch may not have been allergic in this case. Nevertheless, serum IgA was elevated. IgA can be increased in immunologically mediated bullous, itchy skin diseases, such as dermatitis herpetiformis.7 Given the lack of known skin disease and the normal skin exam, the significance of this observation is unclear. A reaction to the morphine salt, i.e., the sulfate, is also a possibility, and it is possible that itch might not occur with other salts, such as morphine hydrochloride. It is also noteworthy that the itch was independent of the route of morphine administration. Hydromorphone hydrochloride, a hydrogenated ketone of morphine, has the same action and uses. It is more potent than morphine on a milligram basis and has a slightly shorter duration of action.3 Reduced itch with hydromorphone hydrochloride compared with morphine sulfate also had been shown when given as an epidural infusion in a randomized, blinded study in 55 adult nonobstetric patients undergoing major surgical procedures.2 Recently, transnasal butorphanol has been suggested as a possible intervention for severe opioid-induced itch which is unresponsive to antihistamines.8 It was postulated that this effect of butorphanol was mediated by it functioning as a competitive antagonist for morphine at the mu-2 receptor. In this case, both morphine and hydromorphone are pure mu-agonist opioids, and a receptor-based explanation for relief of the itch seems unlikely. Oxycodone, oxymorphone, or fentanyl could have been chosen instead of hydromorphone, as they may cause less histamine release.9 Nevertheless, itch has been reported as a side effect of oxycodone and it is possible that opioid-induced itch may not be due to histamine release.10 In our experience, severe opioid-induced itching is an uncommon complication of morphine use. In this case it prevented a good out-
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come. The observation that oral and intravenous hydromorphone provided satisfactory analgesia without troublesome morphine-related itch suggests that opioid rotation may be a useful strategy for patients with severe opioid-induced itch.
References 1. Walsh TD. Prevention of opioid side effects. J Pain Symptom Manage 1990;6:362–367. 2. Chaplan S, et al. Morphine and hydromorphone epidural analgesia. Anesthesiology 1992;77: 1090–1094. 3. Beaver WT. Management of cancer pain with parenteral medication. J Am Med Assoc 1980;244: 2653–2657. 4. Stoelting RK. Pharmacology and physiology in anesthetic practice, 2nd ed. Philadelphia: Lippincott, 1991. 5. Etches RC. Complications of acute pain man-
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agement. In: Anesthesiology clinics of North America: current concepts in acute pain control. Philadelphia: Saunders, 1992;417–433. 6. Davies D. Skin disorders. Textbook of adverse drug reactions, 2nd ed. Oxford University Press, 1981;420–421. 7. Fraki, JE, et al. Comparison of the human skin chymotrypsin-like proteinase with cathespin g and its location within skin. Clin Res 1982;30:584A. 8. Dunteman E, Karanikolas M, Filtos KS. Transnasal butorphanol for the treatment of opioid-induced pruritus unresponsive to antihistamines. J Pain Symptom Manage 1996;12:255–260. 9. Hermens JM, Hanifin JM, Hirshman CA. Comparison of histamine release in human skin mast cells induced by morphine and fentanyl as supplements to nitrous oxide anesthesia. Anesthesiology 1985;62:124–129. 10. Glare P, Walsh TD. Dose-ranging study of oxycodone for chronic pain in advanced cancer. J Clin Oncol 1993;973–978.