Bioavailability, Pharmacokinetics, and Analgesic Activity of Ketamine in Humans

Clements, John A.; Nimmo, W.S.; Grant, I.S.

doi:10.1002/jps.2600710516

Cited by 339 publications

(176 citation statements)

References 19 publications

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“…This dose was based on the equianalgesic potency of oral and parenteral ketamine. 49 Patients were removed from the study if they had intolerable side effects; and-for ethical reasons in this population with short prognoses-they had the choice to exit the study if there was not a 30% reduction in symptoms by day 14.…”

Section: Methodsmentioning

confidence: 99%

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Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

Irwin

Iglewicz

Nelesen

et al. 2013

Journal of Palliative Medicine

138

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Background: Depression and anxiety are prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Ketamine has many properties that make it an interesting candidate for rapidly treating depression and anxiety in patients receiving hospice care. To test this hypothesis, a 28-day, open-label, proof-of-concept trial of daily oral ketamine administration was conducted in order to evaluate the tolerability, potential efficacy, and time to potential efficacy in treating depression and anxiety in patients receiving hospice care. Methods:In this open-label study, 14 subjects with symptoms of depression or depression mixed with anxiety warranting psychopharmacological intervention received daily oral doses of ketamine hydrochloride (0.5 mg/ kg) over a 28-day period. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS), which was used to rate overall depression and anxiety symptoms at baseline, and on days 3, 7, 14, 21, and 28. Results: Over the 28-day trial there was significant improvement in both depressive symptoms (F 5,35 = 8.03, p = 0.002, g 2 = 0.534) and symptoms of anxiety (F 5,35 = 14.275, p < 0.001, g 2 = 0.67) for the eight subjects that completed the trial. One hundred percent of subjects completing the trial responded to ketamine for both anxiety and depression. A significant response in depressive symptoms occurred by day 14 for depression (mean D = 3.5, d = 1.14, 95% CI = 1.09-5.9, p = 0.01) and day 3 for anxiety (mean D = 2.4, d = 0.67, 95% CI = 1.0-3.7, p = 0.004). These improvements remained significant through day 28 for both depression (mean D = 4.0, d = 1.34, 95% CI = 2.3-5.9, p = 0.001) and anxiety (mean D = 6.09, d = 1.34, 95% CI = 3.6-8.6, p < 0.001). Side effects were rare, the most common being diarrhea, trouble sleeping, and trouble sitting still. Conclusions: Patients who received daily oral ketamine experienced a robust antidepressant and anxiolytic response with few adverse events. The response rate for depression is similar to those found with IV ketamine; however, the time to response is more protracted. The findings of the potential efficacy of oral ketamine for depression and the response of anxiety symptoms are novel. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the efficacy and safety of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care or other subject populations.

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Section: Methodsmentioning

confidence: 99%

“…The maximum blood concentration of norketamine is actually greater after oral administration than after parenteral administration. 49 Ketamine has a wide therapeutic range, making overdose difficult. Notably, anesthesia dosing is significantly higher than analgesia and depression dosing.…”

Section: Introductionmentioning

confidence: 99%

Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

Irwin

Iglewicz

Nelesen

et al. 2013

Journal of Palliative Medicine

138

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“…Ketamine is most commonly administered as a continuous low-dose intravenous infusion, however SC infusion is also used, especially in palliative care, with a bioavailability (similar to IM) of approximately 90% (Clements et al, 1982). Sublingual, intranasal (IN) and transdermal routes have also been used for acute pain management (see Section 6).…”

Section: Routes Of Systemic Administration and Bioavailabilitymentioning

confidence: 99%

Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non‐inferiority trial

Cohen

Smit

Andrianopoulos³

et al. 2017

Medical Journal of Australia

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Objectives: This study aimed to assess analgesia provided by acupuncture, alone or in combination with pharmacotherapy, to patients presenting to emergency departments with acute low back pain, migraine or ankle sprain. Design: A pragmatic, multicentre, randomised, assessor‐blinded, equivalence and non‐inferiority trial of analgesia, comparing acupuncture alone, acupuncture plus pharmacotherapy, and pharmacotherapy alone for alleviating pain in the emergency department. Setting, participants: Patients presenting to emergency departments in one of four tertiary hospitals in Melbourne with acute low back pain, migraine, or ankle sprain, and with a pain score on a 10‐point verbal numerical rating scale (VNRS) of at least 4. Main outcome measures: The primary outcome measure was pain at one hour (T1). Clinically relevant pain relief was defined as achieving a VNRS score below 4, and statistically relevant pain relief as a reduction in VNRS score of greater than 2 units. Results: 1964 patients were assessed between January 2010 and December 2011; 528 patients with acute low back pain (270 patients), migraine (92) or ankle sprain (166) were randomised to acupuncture alone (177 patients), acupuncture plus pharmacotherapy (178) or pharmacotherapy alone (173). Equivalence and non‐inferiority of treatment groups was found overall and for the low back pain and ankle sprain groups in both intention‐to‐treat and per protocol (PP) analyses, except in the PP equivalence testing of the ankle sprain group. 15.6% of patients had clinically relevant pain relief and 36.9% had statistically relevant pain relief at T1; there were no between‐group differences. Conclusion: The effectiveness of acupuncture in providing acute analgesia for patients with back pain and ankle sprain was comparable with that of pharmacotherapy. Acupuncture is a safe and acceptable form of analgesia, but none of the examined therapies provided optimal acute analgesia. More effective options are needed. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12609000989246.

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“…In addition to robust and rapid antidepressant effects after a single dose, ketamine has sustained antidepressant effects in depressed patients for 1-2 weeks (Berman et al, 2000;Diazgranados et al, 2010;Price et al, 2009;Zarate et al, 2006). This is surprising because of an approximate 3-h half-life of ketamine in plasma (Clements et al, 1982) and its absence in brain in 24 h. These findings suggest that the neurobiological mechanism underlying the antidepressant effects of ketamine is far more complex than simple antagonism of the NMDA receptor.…”

Section: Introductionmentioning

confidence: 99%

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Yamamoto

Ohba

Nishiyama

et al. 2013

Neuropsychopharmacol

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Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([ 11 C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ 11 C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT 1A -R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [ 11 C]DASB. No significant changes were observed in either 5-HT 1A -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.

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Bioavailability, Pharmacokinetics, and Analgesic Activity of Ketamine in Humans

Cited by 339 publications

References 19 publications

Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non‐inferiority trial

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

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