This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Singla, A. Articles by Mao, J. Search for Related Content PubMed Articles by Singla, A. Articles by Mao, J. Related Collections Pain Medicine Pain Pharmacology

---

ANALGESIA

A Differential Diagnosis of Hyperalgesia, Toxicity, and Withdrawal from Intrathecal Morphine Infusion

Aneesh Singla, MD, MPH^*, Milan P. Stojanovic, MD^*, Lucy Chen, MD^*, and Jianren Mao, MD, PhD^*

From the *Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School; Department of Anesthesia and Critical Care, MGH Pain Center; and Department of Anesthesia and Critical Care, MGH Center for Translational Pain Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Address correspondence and reprint requests to Aneesh Singla, MD, MPH, Department of Anesthesia and Critical Care, 35 Fay St., #E-504, Boston, MA 02118. Address e-mail to asingla{at}partners.org.

Abstract

Opioid-induced hyperalgesia, toxicity, and withdrawal are phenomena that may occur with intrathecal opioid infusion. We present a case in which a patient received intrathecal morphine infusion, and then experienced a clinical course that may have involved hyperalgesia, toxicity, and/or withdrawal. The possible differential diagnosis of opioid-induced hyperalgesia, toxicity, and withdrawal, and its implications in clinical pain management, are discussed.

This report demonstrates the complexity of treating patients with long-term continuous intrathecal opioids when modest adjustment of the intrathecal cocktail results in a paradoxical clinical course.

Opioid-induced hyperalgesia is a pronociceptive phenomenon that could occur with acute or chronic opioid administration. This paradoxical opioid-induced hyperalgesia is likely due to the opioid effects on a variety of cellular targets including N-methyl-d-aspartate (NMDA) receptors, spinal glutamate transporters, and protein kinase C (1,2). Anesthesiologists and pain specialists often encounter the clinical ineffectiveness of opioid analgesics when treating chronic pain caused by tolerance and/or hyperalgesia. Indeed, there have been clinical reports suggesting that chronic opioid use may alter pain sensitivity (3–5). More recently, a prospective clinical pilot study has shown a decreased pain threshold in patients with short-term opioid treatment, indicating that opioid-induced hyperalgesia may be a clinically relevant issue (6). However, other clinical conditions related to opioid therapy, such as opioid toxicity and withdrawal, could confound the clinical observation of opioid-induced hyperalgesia.

Here we present a patient with intrathecal morphine infusion for the treatment of complex regional pain syndrome (CRPS), who developed an episode of increased pain sensitivity suggestive of a hyperalgesic response to intrathecal morphine in the setting of possible opioid toxicity and/or withdrawal.

CASE REPORT

A 49-yr-old, otherwise healthy woman, with a history of CRPS (Type I) of the bilateral lower extremities secondary to multiple knee surgeries had been receiving intrathecal morphine (50 mg/mL)/clonidine (500 µg/mL) infusion for several years, and most recently was receiving 21 mg morphine and 200 µg clonidine intrathecally per day. Despite this continuing intrathecal drug therapy, she presented with increasing pain over the prior month without any recent history of trauma or other new medical issues. After evaluation, we considered the diagnosis of increasing tolerance to intrathecally delivered morphine versus exacerbation of her CRPS. A plan was made to add additional intrathecal medications at the time of pump refill, but to keep the same medications and dosages. Routine troubleshooting was performed, and the intrathecal catheter was verified to be patent through a fluoroscopically guided injection of contrast (Omnipaque-240). Bupivacaine at a concentration of 10 mg/mL was added to her infusion and the pump was set to deliver daily doses of 21 mg of morphine, 200 µg of clonidine, and 4.2 mg of bupivacaine. Bupivacaine was used as an adjunctive drug, and this dose did not induce clinically significant sensory or motor deficit. Because her pump was implanted at an outside institution and the precise length of the catheter was not known, a priming bolus was calculated using a programming device based on the estimated length of the catheter from the fluoroscopic image (catheter insertion site at L3–4 and tip at T12), which was given through the pump to clear the catheter dead space.

She returned later in the day complaining of increased pain. She was seen in the emergency department and given a bolus of her intrathecal medications (0.3 mL of the mixture, equivalent to 15 mg morphine, 60 µg of clonidine, and 3 mg of bupivacaine) under the assumption that the priming bolus might have not yet cleared the catheter dead space. The patient experienced several minutes of decreased pain after this bolus, which was likely due to the pharmacological action of bupivacaine. About 10–15 min later, however, she began to have violent jerking, myoclonic actions and rigors, and complained of increasing pain in her lower extremities. There were no focal findings on neurological examination. A second bolus dose (same as above) provided temporary analgesia again, but the pain returned. Five bolus doses (a total of 75 mg morphine, 300 µg clonidine, and 15 mg bupivacaine) were administered through the intrathecal pump over the next few hours. After each bolus, a similar pattern of initial analgesia (15 min) followed by intense myoclonic jerking and rigors occurred with the patient reporting a significant increase in her pain. Troubleshooting of the device was performed again and it was determined to be in good working order. In addition, the intrathecal infusion solution and its concentration also were confirmed. In an effort to provide an alternative form of analgesia, IV fentanyl (50 µg/mL x 20 mL) was given in 3–5 mL boluses incrementally over 5 min but was not helpful in alleviating her pain.

An urgent magnetic resonance imaging scan was performed but was negative for serious pathology including abscess, granuloma, and cauda equina syndrome. At this point, an IV bolus of 100 mg ketamine was given and the patient immediately had significant pain relief and her myoclonic activity and rigors also stopped. Her pain began to return 30 min after the ketamine administration. Over the next 3 h, she received several IV ketamine boluses (100–200 mg per bolus) totaling 700 mg, each being administered when the analgesic effects began to dissipate. She was admitted to the medical intensive care unit overnight, started on an infusion of 100 mg/h of ketamine along with 2–5 mg/h of midazolam (to prevent the dysphoric and hallucinogenic effects of ketamine) and was comfortable overnight. The following morning, her intrathecal medication was changed to a mixture of clonidine (400 µg/mL)/bupivacaine (10 mg/mL)/ sufentanil (50 µg/mL). She continued to experience good pain control from the ketamine/midazolam infusion at the time of discharge from the medical intensive care unit.

DISCUSSION

We report a case in which intrathecal opioid infusion resulted in a complex clinical condition that required urgent medical assistance and hospitalization. Our initial differential diagnosis of her steadily increasing (chronic) pain was increasing tolerance to intrathecal morphine versus exacerbation of her CRPS. Accordingly, the initial treatment was to increase her intrathecal morphine and clonidine dose with the addition of a small-dose local anesthetic to enhance the analgesic effect after we excluded possible mechanical failure of the pump system. To our surprise, this dose change resulted in the above-reported episode. Although it is not uncommon to encounter various complications in intrathecal opioid therapy, this case prompted us to consider a differential diagnosis of several important etiologies of opioid-related clinical complications, including opioid-induced hyperalgesia, toxicity, and acute opioid withdrawal.

Opioid Withdrawal
Increasing pain (e.g., hyperalgesia) is a sign of acute opioid withdrawal and should be considered in patients receiving opioid therapy. Opioid withdrawal may result from pump failure, catheter malfunction, programming error, and/or erroneous drug concentration (7). In this case, the pump function was confirmed on two separate occasions including fluoroscopic imaging after contrast, as were the drug concentrations. In addition, the patient was discharged home with the same working pump after this episode.

Opioid withdrawal is often accompanied by other symptoms and signs including nausea, ataxia, vomiting, diarrhea, and/or altered sense of smell (8–10). These signs and symptoms can occur within 72 h after opioid withdrawal but were absent in this patient. On the other hand, some of her symptoms were suggestive of opioid withdrawal, such as the increased pain, rigors, and myoclonic activity. Although this patient did have increasing pain, the acuity of her pain increase was most dramatic after the intrathecal bolus with morphine/clonidine/bupivacaine. Because bupivacaine is a local anesthetic and was given at a small dose without causing sensory or motor impairment, adding this drug into the mixture should have helped her analgesia. Moreover, it seems unlikely that IV fentanyl bolus would have not improved withdrawal symptoms and signs had the demonstrated clinical presentation resulted from opioid withdrawal. Therefore, her acute exacerbation of pain and new symptoms (myoclonus, rigors) is most likely attributed to the bolus of intrathecal morphine, but not withdrawal from morphine.

Opioid Toxicity
The presence of myoclonus and rigors after each bolus could suggest the presence of opioid toxicity for several reasons. First, the intrathecal opioid dose was increased (not decreased) after the pump refill, which was verified. Second, clinical symptoms did not improve after a supplemental opioid (fentanyl). Third, ketamine (a proposed NMDA receptor antagonist) was helpful in mitigating the patient’s symptoms. Besides antihyperalgesia, the hypnotic and analgesic effects of ketamine could have masked the symptoms of opioid toxicity. In addition, midazolam could have contributed to reducing the clinical signs of opioid toxicity during the later treatment phase. Of interest to note is that we observed analgesia for about 15 min after each bolus, which we now are attributing to the anesthetic effect of bupivacaine and possibly clonidine. Retrospectively, we could have considered decreasing, rather than increasing, the intrathecal morphine dose as an initial approach to this patient’s treatment had we first suspected possible opioid toxicity and/or hyperalgesia.

Opioid-Induced Hyperalgesia
Another possibility of this patient’s clinical condition may have been related to opioid-induced hyperalgesia. This patient had been receiving intrathecal opioid infusion for several years. This episode of opioid-induced hyperalgesia did not occur until after an intrathecal dose escalation (as little as 10%) was initiated. A possible explanation is that, after a chronic course of opioid therapy, a balance may have been reached between the antinociceptive (inhibitory) effects of opioid (analgesia) and the pronociceptive (excitatory) effects of opioid (hyperalgesia). However, because a chronic course of opioid therapy may also lead to the development of opioid tolerance, the ability for the system to increase the analgesic effect after an opioid dose increase could be limited. On the other hand, even a small increase in opioid may trigger the pronociceptive response leading to an episode of opioid-induced hyperalgesia (11,12).

IV ketamine bolus and infusion improved her clinical condition including pain sensitivity. Both preclinical and clinical studies have indicated that opioid-induced hyperalgesia is likely to be mediated, at least in part, by NMDA receptors (1,2,12). Of interest, a preclinical study demonstrated the antihyperalgesic effect of ketamine in rats exposed to a single intrathecal dose of morphine (13). In addition, previous studies have shown that the effect of NMDA receptor antagonists on hyperalgesia could last beyond their pharmacological duration of action (14), which might at least partially explain why this patient’s clinical condition was well under control even after discontinuation of the ketamine infusion. On the other hand, ketamine may also have reduced neuropathic pain and opioid tolerance in this patient and improved her overall pain condition and responsiveness to opioid analgesics. That IV fentanyl (50 µg/mL x 20 mL), given before the ketamine treatment over 5 min without significant analgesic or other side effects, suggests opioid tolerance had developed at both spinal and supraspinal levels after chronic intrathecal morphine infusion for several years. After ketamine, the switch from intrathecal morphine to sufentanil in this patient significantly increased the opioid’s analgesic effects. This outcome may have been because of incomplete tolerance between different opioid analgesics and/or the reported better analgesic effect from neuraxial sufentanil in patients with opioid tolerance (15), therefore tipping the inhibitory (analgesic) and excitatory (hyperalgesic) balance again in favor of pain relief (the analgesic effect of opioid). This could also explain why the intrathecal sufentanil infusion resumed the analgesic effectiveness even after the ketamine infusion was discontinued.

An interesting preclinical observation is that neuropathic pain and opioid-induced hyperalgesia may share many common cellular elements, which could enhance both neuropathic pain and opioid-induced hyperalgesia through intracellular interactions (16). In this regard, it is possible that opioid-induced hyperalgesia may be more likely to present in those patients with neuropathic pain, which would be consistent with this patient’s clinical pain condition. One article reported a cancer patient receiving 900 mg/d of intrathecal morphine (37 mg/h) who had no analgesia at these doses and then responded to an infusion of ketamine at 30 mg/h (along with fentanyl 75 µg/h and midazolam 1.5 mg/h) (17). It is noted that the effectiveness of ketamine alone should not be considered as a conclusive diagnosis of opioid-induced hyperalgesia, given other effects of ketamine. In addition, hyperalgesia seen during a declining plasma opioid concentration (e.g., during opioid withdrawal) may have a different mechanism from that of the phenomenon seen during escalating opioid doses. The former may be related to an increased cAMP level, whereas the latter is likely due to activation of NMDA receptors (2,11).

In summary, this report demonstrates that clinical conditions related to intrathecal opioid therapy could become complex and difficult to treat. Efforts should be made to distinguish various etiologies such as opioid withdrawal, toxicity, and hyperalgesia. An appropriate differential diagnosis will not only help exclude exacerbation in the patient’s underlying disease but also formulate proper treatment modalities. Given that ketamine provides multiple pharmacological effects, ketamine may be considered as a primary treatment modality under similar clinical conditions discussed in this report. In addition, opioid rotation and/or adding adjunctive medications may also improve the opioid’s analgesic effects and reduce opioid tolerance (18–20). When opioid toxicity and hyperalgesia are considered in patients who are on high opioid doses, decreasing original opioid doses may be considered as a clinical treatment modality.

Footnotes

Accepted for publication August 10, 2007.

REFERENCES

1. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002;22:8312–23[Abstract/Free Full Text]
2. 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 1994;14:2301–12[Abstract]
3. Sjogren P, Jonsson T, Jensen NH, Drenck NE, Jensen TS. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993;55:93–7[Web of Science][Medline]
4. Devulder J. Hyperalgesia induced by high-dose intrathecal sufentanil in neuropathic pain. J Neurosurg Anesthesiol 1997;9:146–8[Web of Science][Medline]
5. Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend 2001;63:139–46[Web of Science][Medline]
6. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006;7:43–8[Web of Science][Medline]
7. Hu K, Connelly DR, Vieira P. Withdrawal symptoms in a patient receiving intrathecal morphine via an infusion pump. J Clin Anesth 2002;14:595–7[Web of Science][Medline]
8. Compton P, Athanasos P, Elashoff D. Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain 2003;4:511–19[Web of Science][Medline]
9. Devulder J, Bohyn P, Castille F, De Laat M, Rolly G. A case of uncommon withdrawal symptoms after a short period of spinal morphine administration. Pain 1996;64:589–91[Web of Science][Medline]
10. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87[Web of Science][Medline]
11. Mao J. Opioid-induced abnormal pain sensitivity. Curr Pain Headache Rep 2006;10:67–70[Medline]
12. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002;100:213–17[Web of Science][Medline]
13. Van Elstraete AC, Sitbon P, Trabold F, Mazoit JX, Benhamou D. A single dose of intrathecal morphine in rats induces long-lasting hyperalgesia: the protective effect of prior administration of ketamine. Anesth Analg 2005;101:1750–6[Abstract/Free Full Text]
14. Mao J, Price DD, Mayer DJ, Lu J, Hayes RL. Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy. Brain Res 1992;576:254–62[Web of Science][Medline]
15. de Leon-Casasola OA, Lema MJ. Epidural bupivacaine/ sufentanil therapy for postoperative pain control in patients tolerant to opioid and unresponsive to epidural bupivacaine/ morphine. Anesthesiology 1994;80:303–9[Web of Science][Medline]
16. Wilson GR, Reisfield GM. Morphine hyperalgesia: a case report. Am J Hosp Palliat Care 2003;20:459–61[Abstract/Free Full Text]
17. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–74[Web of Science][Medline]
18. Sjogren P, Jensen NH, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 1994;59:313–16[Web of Science][Medline]
19. Fine PG. Opioid insights: opioid-induced hyperalgesia and opioid rotation. J Pain Palliat Pharmacother 2004;18:75–9
20. Indelicato RA, Portenoy R. Opioid rotation in the management of refractory cancer pain. J Clin Oncol 2002;20:348–52[Free Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Singla, A. Articles by Mao, J. Search for Related Content PubMed Articles by Singla, A. Articles by Mao, J. Related Collections Pain Medicine Pain Pharmacology