General Hospital Psychiatry 37 (2015) 97.e11–97.e12
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Ziconotide-induced psychosis: a case report Stephanie V. Phan, Pharm.D., B.C.P.P. a,⁎, Julie M. Waldfogel, Pharm.D., C.P.E. b a b
University of Georgia College of Pharmacy, Southwest Georgia Clinical Campus, 1000 Jefferson Street, Albany, GA 31701, USA Pain and Palliative Care, The Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21287, USA
a r t i c l e
i n f o
Article history: Received 12 May 2014 Revised 2 October 2014 Accepted 6 October 2014 Keywords: Ziconotide Drug-induced Psychosis Antipsychotic Adverse effect
a b s t r a c t Ziconotide is used intrathecally in the management of severe chronic pain that contains a warning against neuropsychiatric adverse events. The definition of psychiatric events is broad and management strategies are vague. This case report describesa 49-year-old female who was admitted to the acute psychiatric unit to address auditory hallucinations and paranoid ideation persisting for 3 weeks. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted to treat pain. Upon hospital admission, the pump was infusing at a rate of 4.9 mcg/24 hours. Because the drug could not be immediately discontinued, risperidone 0.5 mg nightly was initiated and subsequently, the pump was drained of ziconotide, rinsed, and refilled with normal saline. The patient reported no hallucinations or apparent delusions several hours later and was eventually discharged with resolution of psychotic symptoms and continuation of risperidone for 10 days. Despite the identification of neuropsychiatric effects, limited information is available to characterize the presentation and guide specific management aside from recommendations to discontinue the infusion and possible use of psychotropic medications or necessity for hospitalization. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide intrathecal infusion. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide from the pump, and role for short-term use of antipsychotics. © 2015 Elsevier Inc. All rights reserved.
1. Background Ziconotide (Prialt) is approved for the management of severe chronic pain in patients for whom intrathecal therapy is warranted yet are intolerant or refractory to other treatments [1,2]. It is a synthetic conopeptide analog derived from the venom of the Conus magnus that selectively targets N-type voltage-gated calcium channels. By blocking calcium influx into nerve terminals, ziconotide reduces pain by interrupting spinal transmission of pain data [1]. There are, however, N-type calcium channels throughout the central nervous system (CNS) and actions at these sites may be responsible for ziconotide's neuropsychiatric adverse effects (NPAEs) [1]. Though ziconotide carries a boxed warning regarding NPAEs, the clinical presentation is broadly defined with vague recommendations toward management. This case highlights the presentation of hallucinations and paranoia without cognitive impairment or altered mental status in a patient receiving ziconotide, treated with a low-dose atypical antipsychotic.
2. Patient case A 49-year-old female was brought to the hospital by her family and admitted to the psychiatric unit to address psychotic symptoms of ⁎ Corresponding author. Tel.: +1-229-312-2154. E-mail address: [email protected] (S.V. Phan). http://dx.doi.org/10.1016/j.genhosppsych.2014.10.001 0163-8343/© 2015 Elsevier Inc. All rights reserved.
hallucinations and paranoia, persisting for approximately 3 weeks. Her past medical history was significant for hypertension, migraines, osteoarthritis, cervical fusion, spinal cord stimulator implantation and complex regional pain syndrome involving the upper extremities related to a previous spinal injury. Her psychiatric history included anxiety and mild depression, treated with psychotherapy. She denied any substance misuse disorders. Upon admission, the patient believed the remote control to be singing to her and heard two voices commenting to each other. She also had paranoid delusions that her husband was trying to kill her. She denied suicidal or homicidal ideation. Upon examination, she was noted to be alert and oriented, exhibiting no abnormal motor activity, normal speech quantity and quality without speech impairment, and with goal-directed thought processes. Fund of information was good, though abstract skills were poor. Memory was poor for recent events, though good for remote events and insight and judgment were intact. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted and was currently infusing at a rate of 4.9 μg/24 h. Concurrent medications on admission included modafinil, triamterene/ hydrochlorothiazide, omeprazole, topiramate, clonazepam, hydromorphone and orphenadrine. Risperidone 0.5 mg po nightly was initiated, and on the following day, the pump was drained of ziconotide, rinsed and refilled with preservative-free normal saline. Hours later, the patient reported no hallucinations and no delusions were noted.
97.e12
S.V. Phan, J.M. Waldfogel / General Hospital Psychiatry 37 (2015) 97.e11–97.e12
At discharge, the psychotic symptoms were considered resolved. The patient stated that she found the hallucinations and delusions to be distressing and preferred treatment with alternative pain medications. She was discharged with a 10-day prescription for risperidone 0.5 mg nightly. 3. Discussion Ziconotide use is contraindicated in patients with a history of psychosis [2]. Additionally, ziconotide may worsen depression and/or increase suicide risk[2]. Initial studies evaluating safety and efficacy of ziconotide identified a high incidence of NPAEs, later determined to be related to the dose and speed of titration [1]. It is recommended that patients be monitored for changes in mood, thoughts or consciousness and that ziconotide be discontinued should serious neurological or psychiatric signs/symptoms appear [2]. In addition, initial doses should not exceed 2.4 μg/day, and optimal dose should be identified with slow titrations occurring no more than two to three times per week [2]. The maximum recommended dose is 19.2 μg/day [2]. Prescribing information notes that management of psychiatric adverse effects may require ziconotide discontinuation, treatment with psychotropic agents and/or acute hospitalization [2]. No specific recommendations for psychotropic agents exist. Though most adverse effects appear to be reversible, the time to reversal may lag due to slow tissue diffusion affecting the offset of medication-induced effects [2]. There is no known antidote [2]. A review of the three randomized control trials of ziconotide reported NPAEs as more neurologic in nature [3]. “Abnormal thinking” was reported; however, this term was defined to include confusion, difficulty concentrating and slowed memory [3,4]. Only one randomized control trial identified serious adverse effects in ziconotide-treated patients that were potentially psychiatric in nature including single cases of agitation, catatonic reaction, thinking abnormal, depression and aphasia [5]. The average time to onset of adverse effects appeared to range from 3.0 to 9.5 days with a time to adverse effect resolution within 1–2 weeks after ziconotide discontinuation [3]. A study after a 1-h intrathecal infusion in chronic pain patients demonstrated that the pharmacokinetics of ziconotide in the cerebrospinal fluid (CSF) are dose proportional and linear. A majority of the 23 patients exhibited no quantifiable ziconotide level in the plasma. Authors concluded that cumulative ziconotide exposure in the CSF was predictive of maximum and cumulative pain relief. The ziconotide CSF area under the concentration–time curve was significantly and positively correlated with nervous system adverse effects (reported as abnormal gait, dizziness, paresthesia and somnolence) indicating that higher exposure was associated with an increased incidence of nervous system effects [6]. The main route of ziconotide clearance from the CSF was postulated to be via rostral-caudal bulk flow of CSF out of the CNS, where ziconotide may be metabolized by peptidases and proteases in the systemic circulation [6,7]. Clearance from the lumbar CSF appeared to have wide interpatient variability in this study [6]. Reports of patients developing anxiety, hypervigilance, avoidant behavior, depressed mood, confusion, hallucinations, agitation and
delirium have been documented [8,9]. In one case series, psychological treatment with relaxation and cognitive-behavioral coping strategies benefitted two of three patients [8]. Symptom resolution took up to 3 weeks [8]. Levin et al. describe a patient who developed acute agitated delirium requiring mechanical ventilation following ziconotide therapy [10]. The delirium persisted 24 days and was unresponsive to benzodiazepines and high-dose haloperidol, eventually requiring electroconvulsive therapy. Full recovery took 3 months [10]. Ziconotide dosing for this patient was within the recommended dose range. The onset of the hallucinations and paranoia was delayed and likely consistent with the pharmacology and pharmacokinetics of ziconotide. The patient was subsequently diagnosed with druginduced psychosis and initial management was to discontinue the offending agent. However, ziconotide removal was delayed while waiting for pain specialists and the patient was significantly distressed about her symptoms; therefore, low-dose risperidone was initiated. Adverse effect resolution appeared to be rapid compared to what has been reported in the literature. Because risperidone may have aided in rapid adverse effect resolution, the patient was prescribed risperidone for an additional 10 days to prevent return of distressing NPAEs.
4. Conclusion Though NPAEs of ziconotide have been highlighted in the literature, the clinical presentation and definition may be broad and unclear. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide managed with drug discontinuation and short-term low-dose risperidone. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide and role for short-term use of antipsychotics.
References [1] Schmidtko A, Lotsch J, Freynhagen R, et al. Ziconotide for the treatment of severe chronic pain. Lancet 2010;375:1569–77. [2] Prialt (ziconotide). Prialt [prescribing information]. Palo Alto, (CA): Jazz Pharmaceuticals, Inc.; 2013. [3] Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebocontrolled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 2006;31:393–406. [4] Staats PS, Yearwood T, Carapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS. JAMA 2003;291:63–70. [5] Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 2006;9:75–86. [6] Wermeling D, Drass M, Ellis D, et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol 2003;43:624–36. [7] Sanford M. Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics. CNS Drugs 2013;27:989–1002. [8] Thompson JC, Dunbar E, Laye RR. Treatment challenges and complications with ziconotide monotherapy in established pump patients. Pain Physician 2006;9: 147–52. [9] Penn RD, Paice JA. Adverse effects associated with the intrathecal administration of ziconotide. Pain 2000;85:291–6. [10] Levin T, Petrides G, Weiner J, et al. Intractable delirium associated with ziconotide successfully treated with electroconvulsive therapy. Psychosomatics 2002;43:63–6.
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Ziconotide-induced psychosis: a case report Stephanie V. Phan, Pharm.D., B.C.P.P. a,⁎, Julie M. Waldfogel, Pharm.D., C.P.E. b a b
University of Georgia College of Pharmacy, Southwest Georgia Clinical Campus, 1000 Jefferson Street, Albany, GA 31701, USA Pain and Palliative Care, The Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21287, USA
a r t i c l e
i n f o
Article history: Received 12 May 2014 Revised 2 October 2014 Accepted 6 October 2014 Keywords: Ziconotide Drug-induced Psychosis Antipsychotic Adverse effect
a b s t r a c t Ziconotide is used intrathecally in the management of severe chronic pain that contains a warning against neuropsychiatric adverse events. The definition of psychiatric events is broad and management strategies are vague. This case report describesa 49-year-old female who was admitted to the acute psychiatric unit to address auditory hallucinations and paranoid ideation persisting for 3 weeks. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted to treat pain. Upon hospital admission, the pump was infusing at a rate of 4.9 mcg/24 hours. Because the drug could not be immediately discontinued, risperidone 0.5 mg nightly was initiated and subsequently, the pump was drained of ziconotide, rinsed, and refilled with normal saline. The patient reported no hallucinations or apparent delusions several hours later and was eventually discharged with resolution of psychotic symptoms and continuation of risperidone for 10 days. Despite the identification of neuropsychiatric effects, limited information is available to characterize the presentation and guide specific management aside from recommendations to discontinue the infusion and possible use of psychotropic medications or necessity for hospitalization. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide intrathecal infusion. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide from the pump, and role for short-term use of antipsychotics. © 2015 Elsevier Inc. All rights reserved.
1. Background Ziconotide (Prialt) is approved for the management of severe chronic pain in patients for whom intrathecal therapy is warranted yet are intolerant or refractory to other treatments [1,2]. It is a synthetic conopeptide analog derived from the venom of the Conus magnus that selectively targets N-type voltage-gated calcium channels. By blocking calcium influx into nerve terminals, ziconotide reduces pain by interrupting spinal transmission of pain data [1]. There are, however, N-type calcium channels throughout the central nervous system (CNS) and actions at these sites may be responsible for ziconotide's neuropsychiatric adverse effects (NPAEs) [1]. Though ziconotide carries a boxed warning regarding NPAEs, the clinical presentation is broadly defined with vague recommendations toward management. This case highlights the presentation of hallucinations and paranoia without cognitive impairment or altered mental status in a patient receiving ziconotide, treated with a low-dose atypical antipsychotic.
2. Patient case A 49-year-old female was brought to the hospital by her family and admitted to the psychiatric unit to address psychotic symptoms of ⁎ Corresponding author. Tel.: +1-229-312-2154. E-mail address: [email protected] (S.V. Phan). http://dx.doi.org/10.1016/j.genhosppsych.2014.10.001 0163-8343/© 2015 Elsevier Inc. All rights reserved.
hallucinations and paranoia, persisting for approximately 3 weeks. Her past medical history was significant for hypertension, migraines, osteoarthritis, cervical fusion, spinal cord stimulator implantation and complex regional pain syndrome involving the upper extremities related to a previous spinal injury. Her psychiatric history included anxiety and mild depression, treated with psychotherapy. She denied any substance misuse disorders. Upon admission, the patient believed the remote control to be singing to her and heard two voices commenting to each other. She also had paranoid delusions that her husband was trying to kill her. She denied suicidal or homicidal ideation. Upon examination, she was noted to be alert and oriented, exhibiting no abnormal motor activity, normal speech quantity and quality without speech impairment, and with goal-directed thought processes. Fund of information was good, though abstract skills were poor. Memory was poor for recent events, though good for remote events and insight and judgment were intact. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted and was currently infusing at a rate of 4.9 μg/24 h. Concurrent medications on admission included modafinil, triamterene/ hydrochlorothiazide, omeprazole, topiramate, clonazepam, hydromorphone and orphenadrine. Risperidone 0.5 mg po nightly was initiated, and on the following day, the pump was drained of ziconotide, rinsed and refilled with preservative-free normal saline. Hours later, the patient reported no hallucinations and no delusions were noted.
97.e12
S.V. Phan, J.M. Waldfogel / General Hospital Psychiatry 37 (2015) 97.e11–97.e12
At discharge, the psychotic symptoms were considered resolved. The patient stated that she found the hallucinations and delusions to be distressing and preferred treatment with alternative pain medications. She was discharged with a 10-day prescription for risperidone 0.5 mg nightly. 3. Discussion Ziconotide use is contraindicated in patients with a history of psychosis [2]. Additionally, ziconotide may worsen depression and/or increase suicide risk[2]. Initial studies evaluating safety and efficacy of ziconotide identified a high incidence of NPAEs, later determined to be related to the dose and speed of titration [1]. It is recommended that patients be monitored for changes in mood, thoughts or consciousness and that ziconotide be discontinued should serious neurological or psychiatric signs/symptoms appear [2]. In addition, initial doses should not exceed 2.4 μg/day, and optimal dose should be identified with slow titrations occurring no more than two to three times per week [2]. The maximum recommended dose is 19.2 μg/day [2]. Prescribing information notes that management of psychiatric adverse effects may require ziconotide discontinuation, treatment with psychotropic agents and/or acute hospitalization [2]. No specific recommendations for psychotropic agents exist. Though most adverse effects appear to be reversible, the time to reversal may lag due to slow tissue diffusion affecting the offset of medication-induced effects [2]. There is no known antidote [2]. A review of the three randomized control trials of ziconotide reported NPAEs as more neurologic in nature [3]. “Abnormal thinking” was reported; however, this term was defined to include confusion, difficulty concentrating and slowed memory [3,4]. Only one randomized control trial identified serious adverse effects in ziconotide-treated patients that were potentially psychiatric in nature including single cases of agitation, catatonic reaction, thinking abnormal, depression and aphasia [5]. The average time to onset of adverse effects appeared to range from 3.0 to 9.5 days with a time to adverse effect resolution within 1–2 weeks after ziconotide discontinuation [3]. A study after a 1-h intrathecal infusion in chronic pain patients demonstrated that the pharmacokinetics of ziconotide in the cerebrospinal fluid (CSF) are dose proportional and linear. A majority of the 23 patients exhibited no quantifiable ziconotide level in the plasma. Authors concluded that cumulative ziconotide exposure in the CSF was predictive of maximum and cumulative pain relief. The ziconotide CSF area under the concentration–time curve was significantly and positively correlated with nervous system adverse effects (reported as abnormal gait, dizziness, paresthesia and somnolence) indicating that higher exposure was associated with an increased incidence of nervous system effects [6]. The main route of ziconotide clearance from the CSF was postulated to be via rostral-caudal bulk flow of CSF out of the CNS, where ziconotide may be metabolized by peptidases and proteases in the systemic circulation [6,7]. Clearance from the lumbar CSF appeared to have wide interpatient variability in this study [6]. Reports of patients developing anxiety, hypervigilance, avoidant behavior, depressed mood, confusion, hallucinations, agitation and
delirium have been documented [8,9]. In one case series, psychological treatment with relaxation and cognitive-behavioral coping strategies benefitted two of three patients [8]. Symptom resolution took up to 3 weeks [8]. Levin et al. describe a patient who developed acute agitated delirium requiring mechanical ventilation following ziconotide therapy [10]. The delirium persisted 24 days and was unresponsive to benzodiazepines and high-dose haloperidol, eventually requiring electroconvulsive therapy. Full recovery took 3 months [10]. Ziconotide dosing for this patient was within the recommended dose range. The onset of the hallucinations and paranoia was delayed and likely consistent with the pharmacology and pharmacokinetics of ziconotide. The patient was subsequently diagnosed with druginduced psychosis and initial management was to discontinue the offending agent. However, ziconotide removal was delayed while waiting for pain specialists and the patient was significantly distressed about her symptoms; therefore, low-dose risperidone was initiated. Adverse effect resolution appeared to be rapid compared to what has been reported in the literature. Because risperidone may have aided in rapid adverse effect resolution, the patient was prescribed risperidone for an additional 10 days to prevent return of distressing NPAEs.
4. Conclusion Though NPAEs of ziconotide have been highlighted in the literature, the clinical presentation and definition may be broad and unclear. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide managed with drug discontinuation and short-term low-dose risperidone. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide and role for short-term use of antipsychotics.
References [1] Schmidtko A, Lotsch J, Freynhagen R, et al. Ziconotide for the treatment of severe chronic pain. Lancet 2010;375:1569–77. [2] Prialt (ziconotide). Prialt [prescribing information]. Palo Alto, (CA): Jazz Pharmaceuticals, Inc.; 2013. [3] Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebocontrolled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 2006;31:393–406. [4] Staats PS, Yearwood T, Carapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS. JAMA 2003;291:63–70. [5] Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 2006;9:75–86. [6] Wermeling D, Drass M, Ellis D, et al. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients. J Clin Pharmacol 2003;43:624–36. [7] Sanford M. Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics. CNS Drugs 2013;27:989–1002. [8] Thompson JC, Dunbar E, Laye RR. Treatment challenges and complications with ziconotide monotherapy in established pump patients. Pain Physician 2006;9: 147–52. [9] Penn RD, Paice JA. Adverse effects associated with the intrathecal administration of ziconotide. Pain 2000;85:291–6. [10] Levin T, Petrides G, Weiner J, et al. Intractable delirium associated with ziconotide successfully treated with electroconvulsive therapy. Psychosomatics 2002;43:63–6.
