Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Levin, T. Articles by Bailine, S. Search for Related Content PubMed Citation Articles by Levin, T. Articles by Bailine, S. Delirium

Intractable Delirium Associated With Ziconotide Successfully Treated With Electroconvulsive Therapy

Received August 15, 2001; revised September 25, 2001; accepted October 2, 2001. From the Department of Consultation-Liaison Psychiatry, Long Island Jewish Medical Center, New Hyde Park, NY. Address correspondence and reprint requests to Dr. Levin, Department of Consultation-Liaison Psychiatry, Long Island Jewish Medical Center, 270-05 76th Ave, New Hyde Park, NY 11040. E-mail: tlevin{at}lij.edu

Key Words: Delirium • Ziconotide • Calcium-Channel Antagonist • Electroconvulsive Therapy

Ziconotide is a new class of non-opioid analgesic¹ that selectively blocks the neuron-specific (N-type), voltage-gated calcium channels, preventing the release of substance P and calcitonin gene-related peptide. A synthetic derivative of the peptide (-conopeptide-MVIIA, found in the venom of a fish-hunting marine snail, it lacks the side effects of tolerance, respiratory depression, and constipation seen with the opioids. A technique for intrathecal delivery of ziconotide to the dorsal horn of the spinal cord, where N-type calcium-receptor sites are concentrated, involves implanting an infusion pump in the anterior abdominal wall with an antibiotic cuffed catheter tunneled subcutaneously and inserted into the intrathecal space via fluoroscopy.² We report a case of severe protracted delirium associated with intrathecal ziconotide that required intubation and ventilation for self-protection and that resolved only after treatment with electroconvulsive therapy (ECT).

Case Report

Mr. B. is a 38-year-old, married, Caucasian, college-educated businessman who was brought to the emergency department in a state of mild confusion. He was ataxic, with a large scalp laceration from a fall at home. Over the course of several hours, he developed a severe agitated delirium requiring physical restraints, with tachycardia of 116 beats per minute, respiratory rate of 24 per minute, temperature of 100.3°F, and blood pressure of 150/90 mm Hg. Treatment with haloperidol (30 mg iv), lorazepam (2 mg iv), and midazolam (6 mg iv) had little effect. He continued to thrash uncontrollably despite the restraints and was incontinent of feces, diaphoretic, and flushed. He was subsequently intubated and paralyzed for his own protection and admitted to the intensive care unit.

Recent medical history relevant to this dramatic presentation was a 7-year history of painful glove-and-stocking peripheral neuropathy of unknown etiology. It was first diagnosed with nerve conduction studies and treated by the pain management service of a major teaching hospital, initially with a tricyclic antidepressant alone and, as the pain grew worse, with a complex polypharmacologic regimen, including imipramine (200 mg/day), gabapentin (1,200 mg/day), mexiletine (900 mg/ day), methadone (40 mg/day), clonazepam (2 mg/day), and ziconotide via an intrathecal pump. Treatment with ziconotide was part of a Phase III drug trial assessing its efficacy in treating chronic pain using an incremental dosing protocol.

On beginning ziconotide, Mr. B. experienced transient urinary retention and had several subsequent episodes, usually when the dose was increased. After taking ziconotide for 2 months, he was pain free for a period of 2 months only. Subsequently, as the dose was increased, his wife noticed episodic and fleeting memory lapses, and in the month before his admission Mr. B. exhibited slow, involuntary, symmetrical muscle twitches that were most apparent as he was dozing off to sleep.

In the 2 weeks before his admission, he became increasingly overwhelmed by "anxiety," and clonazepam was prescribed up to a dose of 2 mg/day, without effect. His intrathecal pump was refilled 22 days before admission. Eight days before admission, the dose was reduced from 0.65 µ/hour to 0.60 µ/ hour because of worsening "anxiety," which was then thought to be a possible side effect of ziconotide.

In the week before admission, the anxiety at times merged with confusion, according to his wife. Two days before admission, for no apparent reason, he crashed his car into a pole but was not injured.

In Mr. B.'s past medical history, type 2 diabetes mellitus was diagnosed at age 36 years, 4 years after the onset of his peripheral neuropathy, and was treated with diet and metformin (Glucophage; 850 mg/day). Essential hypertension and hypercholesterolemia were first diagnosed at age 32 and were well controlled with clonidine (0.1 mg/day) and fenofibrate (200 mg/ day). Mild obesity was treated with sibutramine (Meridia; 10 mg/day). Rectal-prolapse surgery many years previously was complicated by postoperative delirium and hallucinations lasting 24 hours, associated with the use of intravenous meperidine.

With regard to past psychiatric history, Mr. B. reported an episode of seeing spiders shortly after being sent to boarding school at the age of 12 years. Subsequently, he experienced the sensation of bugs crawling under his skin and was admitted to a children's psychiatric ward, where he received neuroleptic therapy for a short time. His teenage years were characterized by transient experimentation with alcohol, cannabis, stimulants, and barbiturates, without evidence of dependence.

Extensive laboratory investigations showed a persistent normocytic, normochromic anemia (hemoglobin 10 g/dL; reticulocytes 3.46%); white blood cell count of 10–12 x10³/µL, without a left shift; urea, creatinine, and electrolytes within the normal range; and elevated creatine phosphokinase (1,557 U/L on admission and thereafter persistently elevated at approximately 500 U/L). An electroencephalogram showed diffuse slowing without focal seizure activity. Twenty-four-hour urinary normetanephrine, metanephrine, vanillymandelic acid, thyroid function, vitamin B12, and folate, as well as computed tomography scan of the brain, were within normal limits. Cerebrospinal fluid (CSF) protein was elevated at 150 mg/dL. CSF and blood cultures were negative. A urine drug screen showed tricyclic antidepressants, methadone, and benzodiazepines in therapeutic concentrations, but no illicit drugs.

After admission to the intensive care unit with acute agitated delirium, Mr. B. remained intubated and ventilated for 2.5 weeks. All previous medications were ceased (except for methadone, to avoid precipitating opioid withdrawal). The intrathecal pump implanted in his anterior abdominal wall containing a reservoir of ziconotide was switched off. His vital signs were persistently abnormal, with low-grade fever of approximately 100°F, tachycardia, and labile blood pressure (200/ 100–90/70 mm Hg).

Four attempts were made to wean Mr. B. off the ventilator. On Day 3, lowering the dose of propofol and cisatracurium infusions resulted in a reemergence of severe psychomotor agitation and delirium, despite a lorazepam infusion at a dose of 4 mg/hour, and he could not be extubated. The agitation was so severe that Mr. B. fractured two toes despite immobilization with four-point leather restraints. Lorazepam was then changed to haloperidol (5 mg/hour iv), and valproate was added on the unsubstantiated hypothesis that Mr. B. might be suffering from a psychotic affective disorder manifesting as agitation. A second attempt at weaning on Day 5 was similarly unsuccessful. The haloperidol was then increased to a maximum dose of 25 mg/hour over the next 4 days, and a third attempt to wean Mr. B. off the ventilator was made on Day 13. Off paralysis, he exhibited striking slow, symmetrical neuromuscular twitches of the limbs at a rate of approximately 12 per minute. These myotonic twitches progressed to agitated delirium over the course of several hours, and Mr. B. was again paralyzed.

On Day 18, ECT was initiated as treatment for intractable delirium, with a Thymatron DGx, using bifrontal placement. Because Mr. B. was already under general anesthesia with propofol and was paralyzed, no further anesthetic agents were used. The machine was set at the highest energy level to override the anticonvulsant effects of propofol. Mr. B. was treated five times over 3 consecutive days (two seizures the first and second days and one on the third day), with adequate seizure responses. Three hours after his last ECT (Day 21 of admission), he was weaned from neuromuscular paralysis. When he showed no signs of psychomotor agitation, he was successfully extubated.

After extubation, Mr. B. exhibited gross delirium, with disorientation to place and time. He had cognitive abnormalities of registration, short- and long-term memory deficits, impaired concentration and executive planning, as well as severe dysarthria. However, he was calm and able to recognize his wife and respond to her reassurance.

Three days later, the delirium had resolved completely. However, Mr. B. remained slightly dysarthric and ataxic, with involuntary asymmetrical myoclonic twitches in all muscle groups. He described his mood as very anxious, although his affect was markedly flat.

One week later, he still had profound retrograde memory deficits. For example, he had no recollection of ever having the ziconotide intrathecal pump inserted into his anterior abdominal wall. He continued to improve, and 1 month later he returned to work on a part-time basis despite persistent retrograde memory lacunae. Three months later, he had fully recovered. Interestingly, the painful peripheral neuropathy that had triggered the whole cascade of events now hardly bothered him.

Discussion

Mr. B.'s delirium was extraordinary because it was characterized by prolonged psychomotor agitation lasting 24 days. The delirium was resistant to high-dose intravenous benzodiazepines and intravenous haloperidol (a conventional treatment for delirium³); even haloperidol at 600 mg/day failed to have any effect. Ziconotide, based on its known side-effect profile and the temporal association between its administration and the onset of symptoms in Mr. B., and in the absence of another pathologic explanation for his symptoms, is the most likely cause of the intractable, agitated delirium observed.

Adverse events reported with ziconotide⁴ are largely neurologic and include delirium, slowed thinking, word-finding difficulties, difficulty concentrating, psychosis, hallucinations, gait abnormality, nystagmus, dizziness, amnesia, headache, somnolence, urinary retention, constipation, nausea and vomiting, postural hypotension, and fever. Of note, abnormal gait, dizziness, nystagmus, and somnolence tend to peak in the first 14 days of therapy, but confusion and amnesia may peak relatively late, after 90 days. Slow titration may reduce the incidence of adverse reactions. Two patients have committed suicide while taking the medication. Sporadic elevation of CPK may occur. Muscle contractions and tremor have also been reported. Although almost all adverse reactions resolved with dose reduction or cessation of the medication, it is noteworthy that confusion may have a delayed resolution taking 10 or more days, and, in one case, more than a month, to resolve.

Mr. B. experienced almost all of the known side effects of ziconotide, including delirium, amnesia, muscle twitches and gross psychomotor agitation, word-finding difficulties, urinary retention, elevated CPK, ataxia, and fever. He also had retrograde amnesia, although this could be a side effect of ECT. The elevated CSF protein may be an effect of ziconotide not previously described. Mr. B. was not anemic before taking ziconotide, and it seems likely that this too is connected to ziconotide toxicity, although the precise mechanism is not clear.

The possibility that the prolonged delirium was caused by one of the other drugs that Mr. B. was receiving seems unlikely. He had been taking mexiletine for a year before his admission. Sibutramine rarely causes a serotonin syndrome. Serotonin syndrome has been associated with the combination of sibutramine and selective serotonin reuptake inhibitors; sumatriptan; dihydroergotamine; opioids such as dextromethorphan, meperidine, and fentanyl (but not methadone); and lithium.⁵ Sibutramine was ceased on admission, making serotonin syndrome unlikely. The possibility of an interaction between sibutramine and ziconotide cannot, however, be ruled out.

Overdose with calcium-channel antagonists can be treated with intravenous calcium⁶ or, less frequently, with glucagon.⁷ It is not known whether intravenous calcium would have been useful in treating the unwanted central nervous system (CNS) effects of ziconotide, bearing in mind that serum calcium levels were within normal limits. Possibly, there was an intracellular calcium deficit within the CNS.

Myoclonic twitches similar to those seen in Mr. B. have been described as a rare side effect (incidence <0.1%) of conventional calcium-channel blocker therapy with verapamil,⁸ diltiazem,⁹ and nifedipine.¹⁰ Rats given ziconotide in high doses demonstrated catatonia (conscious with prolonged psychomotor immobility) of insidious onset as well as a high-frequency tremor (personal communication, Ellis D, Elan Pharmaceuticals, December 2000).

The half-life of ziconotide is 1.3 hours in the plasma¹¹ and 4.6 hours in the CSF, and it readily crosses the blood-brain barrier.¹² This raises the question of the physiologic mechanism of ziconotide-induced delirium. The delirium is often a late side effect of the medication, and its resolution may take weeks to as long as a month. Cessation of ziconotide theoretically means that the drug should be cleared from the circulation within hours, making it implausible that a direct toxic effect is the cause of delirium. One possible explanation is that rostral diffusion of ziconotide into the CSF results in delayed CNS neuronal changes over a period of time. This may be similar to the delayed onset of action of antidepressant medications. In rats, ziconotide does not persist in brain tissue beyond a few hours because it is rapidly removed by tissue peptidase hydrolysis, although it is stable in the CSF, where there appears to be no peptidase hydrolysis.¹¹

Intractable delirium is not well described in the literature; a MEDLINE search produced only one case report. Conventional treatment of delirium involves addressing the underlying cause and using neuroleptic medication to treat the cognitive and behavioral symptoms.¹³

ECT as an effective treatment for delirium has been documented by a number of authors.^14–17 It is effective when treatments are given intensively on a daily basis, described as ECT en bloc. An acute severe delirium is aborted within 2 days, usually with two to four induced seizures. In previous reports, the investigators also used bitemporal electrodes, which are considered to be the most effective method of placement.

Finally, this case serves to remind us that early delirium can be mistaken for anxiety; emergency room physicians and consultation-liaison psychiatrists, in particular, should perform a careful cognitive assessment in this setting.

ACKNOWLEDGMENTS

The authors thank David Ellis, M.D., of Elan Pharmaceuticals for sharing his ziconotide expertise and Max Fink, M.D., for his editorial assistance.

REFERENCES

1. Mathur V: Ziconotide: a new pharmacological class of drug for the management of pain. Seminars in Anesthesia, Perioperative Medicine and Pain 2000; 19:67-75
2. Presley A, Clay DA: Technique for extended intrathecal analgesia trial. Poster Abstract, 19th Annual Scientific Meeting, American Pain Society, November 2-5, 2000, Atlanta, GA
3. Riker RR, Fraser GL, Cox PM: Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22:433-440[Medline]
4. Staats P, Charapata S, Royal M, et al: Safety profile of intrathecal ziconotide: a new non-opioid analgesic. Poster Abstract, 19th Annual Scientific Meeting, American Pain Society, Nov 2-5, 2000, Atlanta, GA
5. Physician's Desk Reference, 54th Edition. Montvale, NJ, Medical Economics Company, 2000, p 1511
6. Howarth DM, Dawson AH, Smith AJ, et al: Calcium channel blocking drug overdose: an Australian series. Hum Exp Toxicol 1994; 13:161-166[Medline]
7. Papadopoulos J, O'Neil MG: Utilization of a glucagon infusion in the management of a massive nifedipine overdose. J Emerg Med 2000; 18:453-455[CrossRef][Medline]
8. Hicks CB, Abraham K: Verapamil and myoclonic dystonia (letter). Ann Intern Med 1985; 103:154
9. Jeret JS, Somasundaram M, Asaikar S: Diltiazem-induced myoclonus. N Y State J Med 1992; 92:447-448[Medline]
10. de Medina A, Biasini O, Rivera A: Nifedipine and myoclonic dystonia (letter). Ann Intern Med 1986; 104:125
11. Bowersox S, Tich N, Mayo M: SNX-111. Drugs Future 1998; 23:152-160
12. Newcomb R, Abbruscato TJ, Singh T, et al: Bioavailability of ziconotide in brain: influx from blood, stability and diffusion. Peptides 2000; 21:491-501[Medline]
13. Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient, 2nd Edition. New York, Oxford University Press, 2000, pp 581-596
14. Kramp P, Bolwig TG: Electroconvulsive therapy in acute delirious states. Compr Psychiatry 1981; 22:368-371[Medline]
15. Strömgren LS: ECT in acute delirium and related clinical states. Convuls Ther 1997; 13:10-17[Medline]
16. Fink M: ECT in delirious states (editorial). J ECT 1999; 15:175-177[Medline]
17. Fink M: The interaction of delirium and seizures. Semin Clin Neuropsychiatry 2000; 5:93-97[Medline]

This article has been cited by other articles:

				E. E. Prommer Ziconotide: Can we use it in palliative care? American Journal of Hospice and Palliative Medicine, September 1, 2005; 22(5): 369 - 374. [Abstract] [PDF]

				V. Bonicalzi and S. Canavero Intrathecal Ziconotide for Chronic Pain JAMA, October 13, 2004; 292(14): 1681 - 1682. [Full Text] [PDF]

				J. Mould, T. Yasuda, C. I. Schroeder, A. M. Beedle, C. J. Doering, G. W. Zamponi, D. J. Adams, and R. J. Lewis The {alpha}2{delta} Auxiliary Subunit Reduces Affinity of {omega}-Conotoxins for Recombinant N-type (Cav2.2) Calcium Channels J. Biol. Chem., August 13, 2004; 279(33): 34705 - 34714. [Abstract] [Full Text] [PDF]

				Z.-P. Feng, C. J. Doering, R. J. Winkfein, A. M. Beedle, J. D. Spafford, and G. W. Zamponi Determinants of Inhibition of Transiently Expressed Voltage-gated Calcium Channels by {omega}-Conotoxins GVIA and MVIIA J. Biol. Chem., May 23, 2003; 278(22): 20171 - 20178. [Abstract] [Full Text] [PDF]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Levin, T. Articles by Bailine, S. Search for Related Content PubMed Citation Articles by Levin, T. Articles by Bailine, S. Delirium

Get information about faster international access.

Privacy Policy

Copyright © 2002 Academy of Psychosomatic Medicine. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us