Iatrogenic Oral Ketamine Overdose in Palliative Care

Abstract

Background:

Optimal pain management in the palliative care setting often requires multiple pharmacological interventions including novel and off-label therapies. Ketamine is an anesthetic agent with increasing evidence supporting its use for pain. Through N-methyl-d-aspartate antagonism and activity at opioid receptors, it is an adjuvant to traditional analgesics with the benefit of being opioid sparing. Ketamine has a wide safety profile with limited reports of overdose. Little is published on supratherpeutic dosing in the pain setting.

Objective:

We report a case of a 41-year-old male with refractory nociceptive and neuropathic cancer-related pain. Conventional therapies were ineffective. Ketamine was initiated to reduce opioid burden and attenuate pain with good response. The patient received an iatrogenic overdose (10 times ordered dose) of the drug. Several self-limited physiologic and psychologic reactions were observed during subsequent monitoring.

Design:

This is a study and analysis of a patient with refractory nociceptive and neuropathic pain syndrome treated with ketamine who sustained an iatrogenic overdose of ketamine.

Conclusions:

Ketamine's use to treat pain is increasing along with its evidence of efficacy. Despite ketamine's wide safety profile, the medication is not without risk, especially in palliative care wherein patients are on multiple drugs with potentially severe interactions. Careful examination of the risks of overdose, especially of the various formulations of the drug, is needed.

Background

Ketamine is currently approved by the U.S. Food and Drug Administration for use as an anesthetic agent. It is used off-label for many indications including major depressive disorder and both acute and chronic pain.¹ Evidence demonstrating ketamine as an effective analgesic and antidepressant is growing as is the literature establishing its effect in the palliative care population.² This population is challenging to treat: patients often have a limited life expectancy in whom standard therapies (i.e., monoaminergic antidepressants and/or opioids) are ineffective, do not have time to work, or carry untenable side effects. In palliative care patients with longer life expectancies, treating pain is increasingly challenging given the opioid crisis, increased survivorship, and long-term and late effects of opioid therapies. Ketamine is a potentially safe agent, with a wide safety margin and rapid onset, making it an attractive alternative to standard therapies.¹ Ketamine treatment is often initiated with intravenous (IV) dosing that is switched to oral, given convenience of outpatient administration.²

Ketamine is primarily an N-methyl-d-aspartate (NMDA) selective noncompetitive antagonist traditionally used to produce hemodynamically stable anesthesia through central sympathetic stimulation.^3–5 In addition, ketamine can activate opioid receptors and affect many other pathways that are involved in pain and mood.⁶ It is popular for procedural sedation, given its rapid onset and cardiovascular stability with preserved airway and breathing reflexes.^3,5 Ketamine is extensively hepatically metabolized by the cytochrome P450 system to the major metabolite norketamine, a noncompetitive NMDA receptor antagonist with one-third the analgesic potency of ketamine. Ketamine may be administered through IV, intramuscular (IM), oral (PO), sublingual (SL), or intranasal (IN) routes, with lower bioavailability for the PO, SL, and IN routes. In the United States, the IV formulation of ketamine contains a racemic mixture of S-ketamine and R-ketamine, with the two enantiomers having different binding affinities. The IV product formulation is utilized for oral dosing of ketamine. Dosing for the treatment of depression, anxiety, and pain is subanesthetic with few adverse effects.^3,7 Data regarding adverse events, side effects, and overdose pertain primarily to IV and IM administration at anesthetic doses; supratherapeutic dosing is most commonly associated with prolonged awakening.^3,8 Ketamine has no known reversal agent; therefore, management of overdose is supportive in nature.

Physiologic side effects include tachycardia, respiratory depression, nausea, hypersalivation, and sedation. Psychological side effects include dysphoria, euphoria, and hallucinations. Given reduced bioavailability, PO, SL, and IN ketamine have presumably lower side effect profiles. Overdoses or supratherapeutic administration of oral ketamine is not widely reported in the literature.

Case

A 41-year-old male with nonsmall cell lung cancer metastatic to bone and brain was admitted with intractable back pain. The patient presented <48 hours after discharge for similar symptoms. The patient's opioid regimen (75 mcg per hour fentanyl patch with 4 mg of oral hydromorphone every four hours as needed for breakthrough pain) had been titrated, but he was discharged without newly initiated adjuvant agents (methocarbamol and tizanidine). He described his pain as mid to low back, throbbing, constant, deep, and aching with paroxysms of a stabbing sensation traveling to his legs as well as spasm and muscle tightness. Palliative care was consulted to help manage his intractable pain and poor functional status: the patient was married with two young children; he was distraught by his pain and newly impaired ability to interact with his children.

Our patient was initially insistent that he neither wanted nor needed long-acting opioid medications. He was agreeable to a hydromorphone patient-controlled analgesia (PCA) device as well as restarting his methocarbamol and tizanidine. Imaging of his chest, abdomen, pelvis, spine, and brain was negative for worsening disease. Despite no evidence of new or progressive disease, spinal metastases were the most likely source of his pain. The patient reported that this pain, although not to this magnitude, had persisted since a diagnostic thoracentesis several months prior. Both neurosurgery and radiation oncology evaluated he was not a candidate for surgical intervention nor for further radiation as it would compromise spinal cord tolerance.

By day 4 of admission, the patient's pain improved to a 7 to 8 out of 10 from a 10 out of 10; he remained on a hydromorphone PCA with >50 mg of IV hydromorphone daily. His rapidly escalating opioid dose with limited benefit prompted a ketamine challenge of a one-time 20 mg IV dose, a recommended test dose per hospital guideline (equating to ∼0.125 mg/kg). The patient's pain decreased from a 9 to a 4 out of 10. The patient was started on 20 mg of oral ketamine every six hours with plans to titrate as tolerated to minimize his opioid dose. Over the next five days, both his ketamine and hydromorphone doses increased, while his methocarbamol and tizanidine remained stable at 1500 mg every six hours and 2 mg at 8 am and 4 pm and 4 mg at bedtime, respectively. By hospital day 9, the patient was receiving 90 mg of IV hydromorphone per day and 35 mg of oral ketamine every 6 hours. The interim between day 4 and day 9 was complicated by emergent cord decompression surgery for a thoracic empyema. Despite this, the patient's pain improved from a 10 out of 10 at admission to a 7 out of 10 on his current regimen, but his IV hydromorphone use increased that was partially attributed to acute postoperative pain. The patient's improved pain, lack of side effects or adverse events, and continued escalating opioid requirement generated a plan to further increase ketamine to 40 mg PO every 6 hours. On hospital day 9, our patient reported a pain score of 3 to 4 out of 10, and a decrease in anxiety about pain, medications, and pain control. Before uptitration, it was discovered that the patient received a dose of 350 mg of oral ketamine as opposed to the prescribed 35 mg.

The dosing error was reported by the pharmacist after dispensing dose from a 100 mg/mL vial as opposed to a 10 mg/mL vial: error was discovered approximately 2 hours after dosing on hospital day 9. Regardless of its relative safety, our patient received a dose 10 times higher than intended and 2.5 times that of his usual daily dose. The half-life of oral ketamine is estimated at 5.6 hours, whereas that of its metabolite, norketamine, is 3.9 hours.^3,4,7,9 Given his supratherapeutic dosing, in cohort with his high opioid usage and other sedative medications, we monitored him for respiratory depression, hypertension, tachycardia, and sedation through continuous pulse oximetry and frequent vital signs for the next 30 hours. Vital sign checks were every 15 minutes for 1 hour, every 30 minutes for 2 hours, once an hour for 2 hours, then every 2 hours. The monitoring time frame was selected based on the half-lives of ketamine and norketamine after oral administration.^3,7,9,10 We also monitored his complete blood count and comprehensive metabolic panel as ketamine has been associated with abnormalities in white and red blood cells in animal studies, rhabdomyolysis and metabolic acidosis in humans with long-term use associated with inflammatory changes, acute and chronic cholestatic liver injury, respectively.^3,7,10,11

Over the course of the next day, the patient's pain remained well controlled. He had several transient episodes of elevated diastolic blood pressure (>90) and tachycardia (110 seconds) that resolved by 18 hours postsupratherapeutic dosing. Approximately 5 hours after dosing, his respiratory rate dropped to 12 breaths per minute versus an average of 18 breaths per minute. Per his wife, who remained at bedside, as well as nursing staff, the patient was more sedated and difficult to arouse for the initial 24 hours. When awake, he was notably dysphoric, prompting benzodiazepine administration with diazepam 5 mg every morning and bedtime with an additional 5 mg available every 6 hours as needed for heightened symptoms. Sixteen hours after receiving the 350 mg dose, his respiratory rate was 14 breaths per minute but his oxygen saturation dropped to 86%, prompting oxygen therapy. All laboratory values remained at baseline. By 48 hours postdose, the patient's mentation returned to baseline, vitals were stable, oxygen was removed, and pain controlled at a 3 out of 10 with 40 mg of oral ketamine every 6 hours and a total daily dose of 85 mg of IV hydromorphone.

Discussion

Ketamine is broadly used for procedural anesthesia and in emergency departments, given its wide safety margin. The elimination half-life for both PO and IV ketamine is just more than five hours. The Cmax for PO ketamine occurs 40 minutes to 2 hours after dosing versus minutes after IV administration.^3,9 Most data regarding supratherapeutic dosing, side effects, and adverse events stem from IV administration.^4,9,12 Multiple sources estimate oral ketamine's median bioavailability at 24%: recent literature on PO ketamine dosing for both pain and depression suggests that 2.5 to 4 times the IV dose are needed for comparable effect.^3,9,13

Pharmacokinetic studies indicate a necessary blood level of ketamine of 100 ng/mL to achieve analgesia after IV administration or 40 ng/mL after PO administration and 200–300 ng/mL for anesthesia regardless of route of administration.^3,9,12 The necessary concentration for norketamine is not known, but postulated to be three times that of ketamine.^3,4,9 Twenty five milligrams of PO ketamine administered in lozenge form reaches a Cmax of 21 ng/mL 2 hours after administration.⁹ Considering only ketamine, a PO dose of 50 mg would be necessary for analgesia and a dose of ∼240 mg for anesthesia. The effect of norketamine may decrease the aforementioned doses as some reports demonstrate equianalgesia due to norketamine's independent effects on analgesia and increased activity with PO dosing.^14,15

These data suggest that for our patient weighing 163 kg, an IV anesthetic dose at 1 to 4.5 mg/kg would be on the order of 150–700 mg of IV ketamine or 375 to 2800 mg of PO ketamine using a conversation ratio based upon best available but limited literature of 2.5–4 mg of oral ketamine to 1 mg IV.^3,9,13 Based upon this information, it is postulated that the 350 mg dose of PO ketamine he received is approximately equivalent to 85 to 140 mg of IV—0.5 mg/kg to nearly 1 mg/kg—the point at which most side effects emerge.⁷ In assessing symptoms, it is important to appreciate PO ketamine's 4- to 12-hour duration of action as well as its elimination half-life of 5 hours.^7,9,10

Our patient recovered from his supratherapeutic dose of ketamine within 48 hours. In the two days after this dose, he experienced improved pain control but notable side effects. We were concerned about ketamine's impact on his liver and bladder function, especially considering his spinal injury, psychomimetic effects, as well as possible role in enhancing tumor growth.^2,3,10 The treatment of our patient's adverse effects was supportive care. An initial euphoria was replaced by prolonged dysphoria and agitation, requiring benzodiazepine therapy. He experienced diastolic hypertension and hypoxemia requiring oxygen. Although these symptoms resolved without intervention, they were significant. Our patient's respiratory symptoms were likely magnified by his high opioid usage. The patient was not on inducers or inhibitors of CYP3A4 or CYP2B6; thus, his plasma concentration of ketamine was neither increased nor reduced by other medications.

Ketamine's extensive first pass metabolism responsible for the 24% oral bioavailability challenges evaluation of potential adverse events. Moreover, little is known on the true activity or interactions of its active metabolite, norketamine.⁹ Norketamine levels measured 10–30 minutes after administration show much greater serum concentrations than that of ketamine: the area under the curve (AUC) for norketamine after oral administration is 5 times greater than after IV and 16.5 times greater than the AUC of ketamine after oral administration.^3,9 This, coupled with induction and inhibition by CYP3A and CYP2B6 enzymes, may have profound effects on side effect profiles and therapeutic utility of oral ketamine. There is less, though more rapid, conversion of ketamine to norketamine and more potential confounders, possibly signaling decreased symptom effect and duration with a decreased side effect profile of oral ketamine. This does not account for the impact of norketamine.

Norketamine is a noncompetitive NMDA receptor antagonist with one-third the anesthetic impact of ketamine.^4,9 This ratio is extrapolated to analgesia but an additional independent role in pain suppression is postulated as it specifically decreases pain perception at the dorsal horn and reverses opioid tolerance by inhibiting nitric oxide synthesis, explaining the lower Cmax of ketamine needed for analgesia after PO administration.⁹

Conclusion

Side effects and adverse events must be considered in the context of delivery route, patient comorbidities, concomitant medications, as well as ketamine's analgesic and anesthetic effects as an NMDA receptor antagonist. Its hyperadrenergic effects of tachycardia, increased cardiac output and hypertension, as well as its anticholinergic effects all contribute to side effect and adverse event profile.^4,7,10 Transient respiratory depression is noted during anesthesia induction at Cmax.¹¹ This patient case highlights the monitoring, supportive management, side effects, and adverse effects associated with an iatrogenic PO ketamine overdose.

Despite ketamine's wide safety margin and limited morbidity and mortality, adverse events can occur.¹⁰ The use of oral racemic ketamine, because of its first pass metabolism and increased norketamine presence, may present new and unique concerns. Extra vigilance is needed in the palliative care population wherein patients are often on multiple sedating and potent medications. Furthermore, increased survival in patients with new symptom clusters requires off label use of potentially harmful drugs, which necessitates a need for further investigation into the immediate and long-term effects of oral ketamine.

Footnotes

Funding Information

No funding was received.

Author Disclosure Statement

No competing financial interests exist.

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