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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4497-4498 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.1462
When Opioids Cause Pain
From the Harry R. Horvitz Center for Palliative Medicine, Cleveland Clinic Health Systems, Cleveland, OH; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY; and the Department of Anesthesia, Stanford University School of Medicine, Stanford, CA Address reprint requests to Mellar Davis, MD, Cleveland Clinic Foundation, 9500 Euclid Ave, R35, Cleveland, OH 44195; e-mail: davism6{at}ccf.org HERE'S THE CASE A 54-year-old African American man with an 8-month history of hepatocellular carcinoma causing spinal cord compression and status, postradiation therapy of the spine, suffered from back pain accompanied by burning and lancinating pain in both thighs. Pain therapy consisted of oral oxycodone extended release 800 mg every 8 hours and rescue doses of oral oxycodone 200 mg every 1 hour as needed for breakthrough pain. Additional medications included dexamethasone 6 mg every 6 hours, pregabalin 150 mg every 8 hours, and levetiracetam 1,500 mg every 12 hours. Three weeks after completing radiation therapy, the patient complained of increasing, generalized burning pain and an exquisite sensitivity to light touch or any type of clothing in contact with his body. The pain was generalized but most prominent in the lower extremities. The patient rated the pain intensity as a 10/10 on a numerical rating scale (NRS; 0 = no pain, 10 = worst pain imaginable). Changing the patient's pain therapy to oral methadone 225 mg every 8 hours and buccal fentanyl 800 µg every 1 hour as needed provided some short-term relief of the burning sensation but the allodynia persisted. Five days later, the patient's burning pain was back to a 10/10 on a NRS and was accompanied by severe touch-evoked allodynia and myocloni of the lower and upper extremities. The patient was unable to perform daily activities. Turning him in bed or putting blankets on him provoked intolerable pain. Changing the patient's pain therapy to intravenous methadone 30 mg/h with intravenous methadone 10 mg every 15 minutes as needed for breakthrough pain provided some short-term relief. However, within 2 days the patient suffered again from generalized severe burning pain (10/10 NRS), allodynia, and myocloni while also becoming delirious. A positron emission tomography scan and magnetic resonance imaging of the total spine demonstrated no major structural change, and an magnetic resonance imaging scan of the head revealed no brain metastases or other intracranial pathology. Intravenous lorazepam 1 mg as needed and intravenous ketamine 1 mg/h were started to alleviate symptoms. Over the course of 1 week, ketamine was increased to 13 mg/h with partial resolution of the myocloni but persistence of the delirious state. Subsequently, intravenous methadone was reduced over 4 to 5 days to 12 mg/h. This resulted in decreased burning pain (5 to 6 of 10 NRS) and reduced allodynia. An attempt to increase the methadone dose aggravated the burning pain as well as the allodynia. The patient was kept on intravenous methadone 12 mg/h, ketamine 13 mg/h, and lorazepam 1 to 2 mg as needed. He died 3 months later on home hospice. His pain remained at 4 to 5 of 10 (NRS) for the last month of his life with neuropathic pain, but less intense allodynia and myocloni-free intervals were of longer duration. His mental status waxed and waned until he died. DISCUSSION A common approach to treating increasing cancer pain in a patient who is otherwise tolerating an opioid therapy is to escalate the opioid dose.1 However, as illustrated by this case, opioid therapy and titration sometimes can worsen, rather than ease, pain. Recent clinical experience and research suggests that some patients experience more pain and/or additional pain symptoms as a consequence of opioid therapy.2-6 This phenomenon has been termed as opioid-induced hyperalgesia (OIH). Phenomenologically, three forms of OIH can be distinguished, resulting either in an increased sensitivity to pain, an aggravation of pre-existing pain or the expression of novel pain symptoms.6 In the recent literature, most attention has been paid to OIH in the context of opioid maintenance therapy or withdrawal. A second form of OIH has been described in the setting of administering very high and escalating doses of opioids. A third form of OIH has been observed in animals when administering ultra-low opioid doses (100 to 1,000 times lower than what seems clinically useful).6 OIH associated with ultra low opioid doses has not been documented in humans and—in this article—will not be further discussed. Evidence from a substantial number of animal and human studies suggests that opioid-induced hyperalgesia, associated with opioid maintenance therapy or withdrawal (OIHMW), involves the upregulation of pain facilitating neuronal pathways at multiple levels of the central and peripheral nervous system.7 Evidence for the existence of OIHMW in humans is provided by studies conducted in patients undergoing surgery, former opioid addicts maintained on methadone, study volunteers undergoing short-term infusion with highly potent opioids or acutely withdrawn from opioids, and patients suffering from chronic low back pain.2-6,8 Acute or chronic dosing of various opioids by different routes has been associated with OIHMW.6 Symptoms are expressed in a dose-dependent fashion and can include an increased sensitivity to painful stimuli, an exacerbation of pre-existing hyperalgesia, and/or an aggravation of pain associated with acute tissue injury. Whether OIHMW can worsen pre-existing chronic pain is not yet known. One important mechanism implicated in the development of OIHMW shares similarities with mechanisms thought to underlay the development of neuropathic pain.9,10 Activation of µ-opioid receptors in the dorsal horn of the spinal cord can lead to hyperalgesia via stimulation of the excitatory amino acid neurotransmitter system. While the stimulation of a µ-opioid receptor initially hyperpolarizes neurons by activating inward rectifying potassium channels (clinically equivalent to analgesic effects), ongoing stimulation of the µ-opioid receptor can result in upregulation of the intracellular messenger phosphokinase C, activation of the N-methyl-D aspartate receptor system, and result in enhanced neuronal excitability (clinically equivalent to hyperalgesic effects).9,10 Another important potential mechanism involves neuronal circuits in the brainstem. The rostral ventral medulla critically modulates the processing of pain signals by exerting descending inhibitory and facilitatory control. Opioid-induced activation of facilitating pathways appears to involve the neurotransmitter cholecystokinin at the level of the brainstem and dynorphin at the level of the spinal cord.11,12 Dynorphin mobilizes intracellular calcium and stimulates release of substance P and glutamate, thereby amplifying pain signals at the level of the spinal cord.12 A second form of opioid-induced hyperalgesia has mostly been observed in cancer patients who receive very high and escalating opioid doses (OIHHD).6 Morphine has been implicated in virtually all reported cases. The predominant symptom of OIHHD is severe allodynia (touch-evoked pain) and is often accompanied by myocloni. Putting a blanket on or gently turning a bed-ridden patient can evoke excruciating pain. OIHHD is unlikely mediated through the opioidergic receptor system. Some experimental evidence in animals suggests that opioids with specific structural characteristics (eg, phenanthrene) inhibit glycinergic inhibition at the level of the spinal cord, thereby inducing a strychnine-like excitatory intoxication.13,14 Accordingly, administration of an opioid-antagonist does not alleviate OIHHD. Escalating the dose of the opioid causing OIHHD aggravates symptoms, while reducing the dose reduces symptoms.6 Finally, switching from a phenanthrene (morphine) derivative to a piperidine derivative (eg, fentanyl) or methadone has been reported to attenuate or resolve OIHHD. The present case represents another clinical example of opioid-induced hyperalgesia in the setting of administering OIHHD. While virtually all reported cases of OIHHD have been attributed to morphine administration, this patient developed the condition while treated with escalating doses of methadone. From a clinical perspective, this case report emphasizes the importance of considering OIH if analgesic treatment effects are lost in the context of aggressive opioid titration and are unexplained by cancer progression, or when generalized or expanded pain complaints are reported in the face of rapid opioid titration. While OIH associated with OIHHD seems to be quite rare, if it is suspected, then dose reduction, opioid rotation, or complete detoxification from an opioid should be considered. The possibility that OIH may limit the utility and dose of opioid therapy also emphasizes the value of alternative methods of pain control. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS We thank Joan Scharf for assistance in preparing this manuscript. This study is a part of the WHO Project in palliative medicine. NOTES Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. REFERENCES 1. Hanks G, De Conno F, Cherny N, et al: Morphine and alternative opioids in cancer pain: The EAPC recommendations. Br J Cancer 84:587-593, 2001[CrossRef][Medline] 2. Chu L, Clark DJ, Angst M: Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study. J Pain 7:43-48, 2006[CrossRef][Medline] 3. Compton P, Athanasos P, Elashoff D: Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: A preliminary study. J Pain 4:511-519, 2003[CrossRef][Medline] 4. Compton P, Charuvastra VC, Kintaudi K, et al: Pain responses in methadone maintained opioid abusers. J Pain Symptom Manage 20:237-245, 2000[CrossRef][Medline] 5. Angst MS, Koppert W, Pahl I, et al: Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 106:49-57, 2003[CrossRef][Medline] 6. Angst M, Clark JD: Opioid induced hyperalgesia. Anesthesiology 104:570-587, 2006[CrossRef][Medline] 7. King T, Ossipov MH, Vanderah T, et al: Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals 14:194-205, 2005[CrossRef][Medline] 8. Guignard B, Bossard AE, Coste C, et al: Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 93:409-417, 2000[CrossRef][Medline] 9. Mao J, Price DD, Mayer DJ: Thermal hyperalgesia in association with the development of morphine tolerance in rats: Roles of excitatory amino acid receptors and protein kinase. C J Neurosci 14:2301-2312, 1994 10. Mayer D, Mao J, Holt J, et al: Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci U S A 96:7731-7736, 1999 11. Xie J, Herman DS, Stiller CO, et al: Cholecystokinin in the rostral ventromedial medulla mediates opioid induced hyperalgelsia and antinociceptive tolerance. J Neurosci 25:409-416, 2005 12. Gardell LR, Wang R, Burgess SE, et al: Sustained morphine exposure induces a spinal dynorphin dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 22:6747-6755, 2002 13. Hara N, Minami T, Okuda-Ashitaka E, et al: Characterization of nociceptin hyperalgesia and allodynia in conscious mice. Br J Pharmacol 121:401-408, 1997[CrossRef][Medline] 14. Werz M, Macdonald RL: Opiate alkaloids antagonize postsynaptic glycine and GABA responses: Correlation with convulsant action. Brain Res 236:107-119, 1982[CrossRef][Medline] Submitted September 13, 2006; accepted April 4, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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