Anesthesiologists are prepared for the common side effects of opioids, including respiratory depression, constipation, and muscle rigidity.1,2 However, rare side effects like catatonia can pose diagnostic and therapeutic challenges.

Catatonia is a neuropsychiatric syndrome featuring catalepsy, altered mental status (AMS), akinesia, posturing, and mutism.3 Diagnosis requires 3 or more of the following characteristics: stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerism, stereotypy, agitation, grimacing, echolalia, and/or echopraxia.4 Motor symptoms result from dopamine hypoactivity in the basal ganglia-thalamocortical circuits,5 with potential serotonin and gamma-aminobutyric acid (GABA) involvement.6 Catatonia usually presents alongside psychiatric disease like schizophrenia but can occur in other medical conditions.3,4 Incidence varies depending on the diagnostic criterion utilized, but it commonly affects adult women.3 Severity ranges from simple to malignant catatonia potentially leading to cardiac, respiratory, and renal complications, thromboembolism, and death.5 Thus, early recognition and treatment are essential.

Opioids can cause catatonia7; however, this reaction is rare and underrepresented in the literature. We present a case of opioid-induced catatonia to inform providers of its presentation and management so it may be included in their list of differential diagnoses. This article adheres to Enhancing the Quality and Transparency Of Health Research (EQUATOR) guidelines. Written Health Insurance Portability and Accountability Act authorization was obtained for this publication.

CASE DESCRIPTION

An 81-year-old woman, American Society of Anesthesiology class III, with chronic kidney disease stage-III (CKD-III) and anxiety on 25 mg sertraline underwent surgical resection of a recurrent retroperitoneal liposarcoma. Past anesthesia complications included postoperative nausea and vomiting.

Preoperatively, an epidural catheter with 0.125% bupivacaine was placed. Intraoperatively, the patient was intubated with 10 mg cisatracurium and underwent general anesthesia receiving isoflurane, 300 mcg fentanyl, 0.4 mg hydromorphone, and 53.35 mg ketamine. A phenylephrine infusion managed blood pressure. The procedure lasted 7 hours. She was extubated and sent to recovery.

Postoperatively, the patient was initially stable but became unresponsive with rigidity and extensor posturing after 30 minutes. A code stroke was activated. She had fixed pinpoint pupils prompting administration of 3 0.04 mg doses of naloxone, and she became fully responsive with a nonfocal examination. Subsequent head computerized tomography scan was negative. Two hours later, the patient again became rigid and unresponsive prompting epidural cessation and teleneurology consultation. Vitals and laboratory values are displayed in Tables 1, 2, respectively. The patient had a blank stare, pupils were 1 to 2 mm and slowly reactive, and no nystagmus or eye deviation was present. She was nonverbal with her jaw clenched shut. All extremities had extensor posturing with sustained posture of her upper extremities when her shoulders were flexed to 90° against gravity. Babinski was negative bilaterally. She demonstrated minimal command following, no withdrawal to painful stimuli, and no extra movements such as clonus. The neurologist’s differential diagnosis included catatonia of metabolic/toxic etiology.

Table 1. - Patient Vital Signs during Catatonic Event Vital signs Measurement Blood pressure 185/93 Respiratory rate (breaths per minute) 13 Heart rate (beats per minute) 66 Temperature (ºC) 36.5 Oxygen saturation (%) 95–100a

aAdministered 2 L of oxygen via nasal cannula.

Table 2. - Patient’s Laboratory Values During Catatonic Event Laboratory panel Laboratory value Result Basic metabolic panel Glucose (mg/dL) 227 ↑a Sodium (mmol/L) 134 ↓ Potassium (mmol/L) 4 Chloride (mmol/L) 99 Anion gap 12 BUN (mg/dL) 10 Creatinine Serum (mg/dL) 0.76 eGFR (mL/min/1.72 m2) 79 ↓ Calcium (mg/dL) 8.6 ↓ Magnesium (mg/dL) 1.4 ↓ Complete blood count WBC (10 * 3/uL) 10.2 Hemoglobin (g/dL) 11.3 ↓ Hematocrit (%) 34.2 ↓ MCV (fL) 88.5 Arterial blood gas pH 7.39 pco 2 (mm Hg) 42.9 po 2 (mm Hg) 154 ↑a Chemistry, other Lactic acid (mmol/L) 2.3 ↑

a↑ and ↓ symbols represent abnormally high and low values, respectively.

Given her prior response to naloxone, the patient received another 0.04 mg and a naloxone infusion. She was administered a 1 mg lorazepam challenge. Upon admission to the intensive care unit, the patient was awake, alert, and conversing appropriately with resolution of catatonia. The epidural was restarted, and the naloxone infusion continued for 8 hours. The patient was discharged home in good condition on postoperative day eight.

DISCUSSION

This case was concluded to be opioid-induced catatonia secondary to our patient’s response to naloxone; however, other diagnoses and mechanisms will be considered in this discussion. We identified 6 case reports6,8–12 and 3 rat studies7,13,14 of opioid-related catatonia for comparison to the literature. We aim to fill the gap in the literature regarding opioid-induced catatonia to aid in early recognition and prevention.

Differential Diagnoses

Neuroleptic malignant syndrome (NMS) is a movement disorder emergency associated with dopaminergic blocking agents. Its mechanism is related to dopamine hypoactivity in the central nervous system (CNS),5 like catatonia. Interestingly, catatonia can be a presenting feature of NMS, often making the 2 indistinguishable.5 While our patient exhibited muscle rigidity and AMS seen in NMS, she lacked key features of hyperthermia and autonomic instability and did not meet diagnostic criteria.5

Serotonin syndrome (SS) is a CNS toxicity that occurs with serotonergic agents, producing cognitive, autonomic, and neuromuscular symptoms.5 While typically resulting from multiple serotonergic agents and/or overdose, SS with monotherapy at therapeutic doses has been reported,5 as in our patient on sertraline. Our patient did not meet SS diagnostic criteria, as she lacked clonus, agitation, diaphoresis, tremor, or hyperthermia.5 Nonetheless, serotonin may play a role in catatonia, as suggested by a case of catatonia from tramadol and meperidine by Huang et al,6 and a case of fentanyl-induced rigidity in a patient on venlafaxine by Roy and Fortier.12

The administration of ketamine, although low dose, may be a contributing factor in this case. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, is hepatically metabolized and renally excreted.2 Catalepsy with dilated pupils and slow nystagmus may be seen with induction doses.2 Studies have claimed naloxone reverses ketamine effects in rats, suggesting ketamine may also stimulate opioid receptors.14 Newer research proposes that ketamine’s antidepressant effects may depend on opiate receptor agonism.15 However, these findings lack consistent replication and demonstration in humans10; therefore, more clinical trials are needed.15 Additionally, our patient exhibited opioid-associated pinpoint pupils rather than ketamine-related nystagmus. Although a ketamine-opioid relationship may contribute to a complex catatonia mechanism through shared effects on opioid receptors, available literature and our patient’s presentation support an opioid-centered etiology in this case.

Muscle rigidity is a known side effect of opioids2 and a potential differential in our patient. Roy and Fortier12 reported a case of truncal rigidity from low-dose fentanyl and meperidine during anesthesia emergence in a woman on venlafaxine that resolved with naloxone—similar to our case. However, in contrast, our patient had rigid extremities and displayed markedly different clinical characteristics consistent with catatonia, as aforementioned.12 Interestingly, respiratory depression, a common opioid side effect,1,2 was absent in both cases, suggesting neither patient had toxic doses despite their adverse reactions; Engquist et al also described this phenomenon.9 Ultimately, the current case better aligns with catatonia than opioid-induced muscle rigidity, although both reactions may involve central action with dopaminergic and serotonergic mechanisms.2,12

Opioid-Induced Catatonia

Opioids act on mu, kappa, and delta receptors,1,2 found even in the basal ganglia where they inhibit dopamine release,1,7,13 and affect movement. They distribute into the tissues and CNS and—like ketamine—are hepatically metabolized and renally excreted. Opioid half-lives increase in patients with liver or kidney disorders1,2 like our patient with CKD-III. Opioid metabolites, including those of fentanyl and hydromorphone, may accumulate in renal disease, causing prolonged action and toxicity, especially in women and older patients.2 As aforementioned, catatonia likely results from dopamine inhibition with serotonergic and GABA contributions.5,6 Considering this multifactorial nature, fentanyl, hydromorphone, ketamine, and sertraline in our patient may have combined to cause her catatonia, with opioids as the leading culprit as illustrated by her response to naloxone.

Naloxone, an opioid-receptor antagonist, has a duration of action of 1 to 2 hours—shorter than most opioids—so multiple doses may be required to maintain effect.1,2 This explains our patient’s initial response to naloxone with subsequent regression into catatonia. Assuming she could not renally clear the opioids, once the naloxone wore off, catatonia was reproduced, requiring additional doses. Di Rosa and Di Rosa reported a similar phenomenon where naloxone transiently treated loperamide-induced catatonia due to its relatively shorter half-life.8 Standard catatonia treatment involves benzodiazepines and electroconvulsive therapy, though the underlying diagnosis ultimately dictates treatment and outcome.3 Our patient’s clear therapeutic response to naloxone implicates opioids as the main catatonia cause.

Our case is unique in that our patient’s catatonia presented and resolved within hours, unlike the typical prodrome of days to weeks.5 This could be attributed to fentanyl’s shorter duration of action compared to morphine subtypes.2 Most published opioid-induced catatonia cases involved longer acting subtypes like methadone,5 meperidine and tramadol,6 loperamide,8 or epidural morphine.9 Studies more often utilized morphine7,14 over fentanyl13 to induce catatonia in rats. Yeoh et al11 identified only 4 of 108 cases due to opioids alone, with 2 resulting from opioid withdrawal rather than intoxication. Therefore, our case may be the first of its kind to describe acute catatonia after fentanyl and hydromorphone administration.

Limitations

Catatonia standardization scales were not utilized in diagnosing this case; however, a neurologist from our institution made the diagnosis. While the neurology examination was conducted over video call, the neurologist was able to make a clear diagnosis by guiding us through the examination.

CONCLUSIONS

Opioid-induced catatonia is a rare and underrecognized syndrome, highlighting the need for further understanding of underlying mechanisms and risk factors. While opioids are discussed as the main culprit in this case, catatonia is likely multifactorial and may involve interactions between medications like opioids, ketamine, and serotonergic agents. Knowledge of these factors may have revealed our patient’s diagnosis during her initial catatonic state, preventing her second catatonic episode. Fortunately, our patient’s catatonia resolved without lasting complications. We hope this case raises awareness among anesthesiologists to consider if opioids are appropriate for vulnerable patients taking medications that may predispose them to catatonia in the perioperative period and beyond.

Patient Perspective: The patient has no memory of the catatonic event and does not wish to know about the event. She currently has no comment.

DISCLOSURES

Name: Laura A. Ketigian, DO.

Contribution: This author contributed to patient treatment, literature search, manuscript preparation, and submission.

Name: Shantanu S. Kidambi, MD.

Contribution: This author contributed to patient treatment, literature search, manuscript preparation, and submission.

This manuscript was handled by: Markus M. Luedi, MD, MBA.

ACKNOWLEDGMENTS

We thank Rajeev S. Iyer, Associate Professor of Anesthesiology at the University of Pennsylvania, Philadelphia, for his expert suggestions on this case report.

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