University of Groningen
Through ketamine fields Viana Chaves, Tharcila
DOI:
10.33612/diss.107955714
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Through ketamine fields
pain and afterglow
by
Tharcila Chaves
Through ketamine fields: pain and afterglow
ISBN printed book 978-94-034-2237-4
ISBN pdf version 978-94-034-2236-7
Cover design and thesis layout Elisa Calamita, persoonlijkproefschrift.nl
Printed by Ipskamp Printing, proefschriften.net
Printed on recycled paper
Copyright © 2019 Tharcila Viana Chaves
All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any way or by any means without the prior permission of the author, or when applicable, of the publishers of the scientific articles.
Through ketamine fields
Pain and afterglow
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 18december2019 om 12:45 uur
door
Tharcila Viana Chaves
geboren op 13 oktober 1981te Santo André, Brazilië
Through ketamine fields
Pain and afterglow
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 18december2019 om 12:45 uur
door
Tharcila Viana Chaves
geboren op 13 oktober 1981te Santo André, Brazilië
Paranimfen Lemke Kraan Olaf Gorter Promotor
Prof. dr. B. Wilffert
Co-promotor Prof. dr. Z.M. Sanchez
Beoordelingscommissie Prof. dr. A.J.M. Loonen Prof. dr E.N. van Roon Prof. dr. B.W.J.H. Penninx
Paranimfen Lemke Kraan Olaf Gorter Promotor
Prof. dr. B. Wilffert
Co-promotor Prof. dr. Z.M. Sanchez
Beoordelingscommissie Prof. dr. A.J.M. Loonen Prof. dr E.N. van Roon Prof. dr. B.W.J.H. Penninx
Contents
Chapter 1 Introduction 9
From the dance floor to the mainstream scientific research Aims and outline of this thesis
Chapter 2 Oral ketamine for the treatment of pain and treatment-
resistant depression 17
Chapter 3 Special features of special K: applications for pain and
depression treatments 37
Chapter 4 The use of ketamine to cope with depressive symptoms: a qualitative analysis of the discourses posted on a popular online forum
49
Chapter 5 Ketamine as a new management tool for persistent physical
and mental pain 71
Chapter 6 Overdoses and deaths related to the use of ketamine and its
analogues: a systematic review 81
Chapter 7 General discussion 105
Addendum Appendix 1: Table - Ketamine for depression studies
(supplementary content of chapter 2) 118
Appendix 2: Table – Ketamine for pain studies
(supplementary content of chapter 2) 146
Appendix 3: References list of the tables presented in
appendices 1 and 2 168
Summary 176
Samenvatting (summary in Dutch) 178
Resumen (summary in Spanish) 181
Resumo (summary in Portuguese) 183
Résumé (summary in French) 185
Publication list of Tharcila Chaves 187
About the author 188
Acknowledgements 189
Chapter 1
Introduction
10
Chapter 1From the dance floor to the mainstream scientific research
We are living a psychedelic renaissance. It is characterised by the use of psychedelic substances to treat different types of disorders (such as depression, drug dependence, chronic pain, and post-traumatic stress disorder - PTSD) under medical surveillance and based in growing scientific evidence. In this thesis, the focus is on ketamine.
However, several other psychedelic substances are showing striking results in managing different sort of disorders. In order to illustrate it, two examples are essential: (a) psilocybin (the main psychoactive compound of the so-called “magic mushrooms”, i.e. mushrooms from the biological genus Psilocybe, among others) for the treatment of depression and (b) MDMA (3,4-methylenedioxymetamphetamine) for PTSD management.
Psychedelic drugs have been used by several cultures all around the world for millennia. The use of peyote (active compound: mescaline), iboga (ibogaine), ayahuasca (N,N-Dimethyltryptamine - DMT), and other naturally occurring plants can be traced back to ancient history (1, 2). Psilocybin is a naturally occurring alkaloid found in some specific mushrooms. Controlled, double-blind clinical trials in healthy volunteers show that, under supportive conditions, psilocybin can cause deeply personally meaningful experiences. Psilocybin is a classic psychedelic with a history of use in psychotherapy because it aids emotional insight by lowering psychological defences (3-5). A recent clinical trial that tested the use of psilocybin for the management of treatment-resistant depression (TRD) showed that tolerability to psilocybin is good, with large effect sizes and symptom improvements that appeared rapidly and remained significant six months post-treatment (3).
Petri et al. (2014), presenting a new method to analyse brain networks called
“homological scaffolds”, compared the resting-state functional brain activity in fifteen healthy volunteers after intravenous infusion of placebo or psilocybin. The results show that the structure of the brain’s functional patterns undergoes a dramatic change post-psilocybin, as represented by figure 1.1.
According to Petri et al. (2014), “the homological scaffolds represent a new measure of topological importance of edges in the original system […]”. They applied this method to a functional magnetic resonance imaging dataset comprising a group of subjects injected with placebo and another injected with psilocybin.
Their findings imply that the brain does not simply become a random system after
psilocybin injection, but instead retains some organisational features, albeit different
from the normal state. This supports the idea that psilocybin disrupts the normal
organisation of the brain with the emergence of strong, topologically long-range
functional connections that are not present in a normal state (6).
11
Introductionthan fixed structural ones as may be the case for acquired synaesthesia [52]. Broadly consistent with this, it has been reported that subjects under the influence of psilocybin have objectively worse colour perception performance despite subjectively intensified colour experience [53].
To summarize, we presented a new method to analyse fully connected, weighted and signed networks and applied it to a unique fMRI dataset of subjects under the influence of mushrooms. We find that the psychedelic state is associ- ated with a less constrained and more intercommunicative mode of brain function, which is consistent with descriptions of the nature of consciousness in the psychedelic state.
7. Methods
7.1. Dataset
A pharmacological MRI dataset of 15 healthy controls was used for a proof-of-principle test of the methodology [54]. Each subject was scanned on two separate occasions, 14 days apart. Each scan consisted of a structural MRI image (T1-weighted), followed by a 12 min eyes-close resting-state blood oxygen-level-dependent (BOLD) fMRI scan which lasted for 12 min. Placebo (10 ml saline, intravenous injection) was given on one occasion and psi- locybin (2 mg dissolved in 10 ml saline) on the other. Injections were given manually by a study doctor situated within the scan- ning suite. Injections began exactly 6 min after the start of the 12-min scans, and continued for 60 s.
7.1.1. Scanning parameters
The BOLD fMRI data were acquired using standard gradient-echo EPI sequences, reported in detail in reference [54]. The volume repetition time was 3000 ms, resulting in a total of 240 volumes acquired during each 12 min resting-state scan (120 pre- and 120 post-injection of placebo/psilocybin).
7.1.2. Image pre-processing
fMRI images were corrected for subject motion within individual resting-state acquisitions, by registering all volumes of the
functional data to the middle volume of the acquisition using the FMRIB linear registration motion correction tool, generating a six-dimension parameter time course [55]. Recent work demon- strates that the six parameter motion model is insufficient to correct for motion-induced artefact within functional data, instead a Volterra expansion of these parameters to form a 24 parameter model is favoured as a trade-off between artefact cor- rection and lost degrees of freedom as a result of regressing motion away from functional time courses [56]. fMRI data were pre-processed according to standard protocols using a high-pass filter with a cut-off of 300 s.
Structural MRI images were segmented into n ¼ 194 cortical and subcortical regions, including white matter cerebrospinal fluid (CSF) compartments, using FREESURFER(http://surfer.nmr.
mgh.harvard.edu/), according to the Destrieux anatomical atlas [57]. In order to extract mean-functional time courses from the BOLD fMRI, segmented T1 images were registered to the middle volume of the motion-corrected fMRI data, using bound- ary-based registration [58], once in functional space mean time-courses were extracted for each of the n ¼ 194 regions in native fMRI space.
7.1.3. Functional connectivity
For each of the 194 regions, alongside the 24 parameter motion model time courses, partial correlations were calculated between all couples of time courses (i,j), non-neural time courses (CSF, white matter and motion) were discarded from the resulting functional connectivity matrices, resulting in a 169 region corti- cal/subcortical functional connectivity corrected for motion and additional non-neural signals (white matter/CSF).
7.2. Persistent homology computation
For each subject in the two groups, we have a set of persistence diagrams relative to the persistent homology groups Hn. In this paper, we use the H1 persistence diagrams of each group to construct the corresponding persistence probability densities for H1cycles.
Filtrations were obtained from the raw partial-correlation matrices through the PYTHONpackage Holes and fed to javaplex [46] via a Jython subroutine in order to extract the persistence
(a) (b)
Figure 6. Simplified visualization of the persistence homological scaffolds. The persistence homological scaffolds Hplap (a) and Hpsip (b) are shown for comparison.
For ease of visualization, only the links heavier than 80 (the weight at which the distributions in figure 5a bifurcate) are shown. This value is slightly smaller than the bifurcation point of the weights distributions in figure 5a. In both networks, colours represent communities obtained by modularity [49] optimization on the placebo persistence scaffold using the Louvain method [50] and are used to show the departure of the psilocybin connectivity structure from the placebo baseline.
The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration. A labelled version of the two scaffolds is available as GEXF graph files as the electronic supplementary material. (Online version in colour.)
rsif.r oy alsocietypublishing.org J. R. Soc. Interfa ce 11 :20140873
8
Figure 1.1: Simplified visualisation of the homological scaffolds: (left) placebo and (right) psilocybin scaffolds. The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration (6).
Another substance that has been showing interesting results in the management of some mental disorders is MDMA. It is different than psilocybin in regard to its non-natural origin. From its roots as an agent to assist psychotherapy in the 1970s and 80s, to its wide scale popularity as the recreational drug “ecstasy” in the rave scene of the 90s, to its contemporary re-emergence as a potential tool for treating PTSD, the controversy around the medical use of MDMA is so big that the debate about its risks and safety is steeped in political issues that threaten to undermine the basic principles of evidence-based medicine. MDMA is emerging as the leading drug in announcing this new form of medical treatment: psychedelic drug-assisted psychotherapy for the treatment of anxiety-based disorders (1).
Psychiatrists and psychotherapists in the United States (in the 1970s until 1985) and Switzerland (between 1988 and 1993) used MDMA legally as a prescription drug to enhance the effectiveness of psychotherapy (7). But it was not until 2010 that Michael Mithoefer, working with the Multidisciplinary Association for Psychedelic Studies, would publish the world’s first randomised controlled study testing MDMA- assisted therapy against placebo, without any evidence of harm (8). MDMA has been researched for its potential role in treating PTSD, a severe anxiety-based psychiatric
1
12
Chapter 1disorder, with a high level of treatment-resistance, and high rates of mortality from suicide (1).
Finally, this psychedelic revival also brings ketamine, which has proven to be useful for the rapid relief of depressive symptoms, for providing an acute interruption of suicidal intent, and for the control of agitated suicidal and aggressively psychotic individuals in the emergency room setting (9). It is the first modern legal psychedelic medicine in use. It has been used as an anaesthetic since the 1960s. Ketamine hydrochloride was invented in 1962 by the American pharmacist Calvin Stevens at the Wayne State University, in the United States. Like all the arylcyclohexylamines (the chemical group that ketamine belongs to), it blocks N-methyl-D-aspartate (NMDA) receptors, preventing them from being activated by the neurotransmitter glutamate (10). More about its mechanism of action is presented in chapters 2, 3 and 5.
In 1964, ketamine was given to a human being for the first time by Edward
Domino (11). It was found to be a potent psychedelic drug, and the effects were
described as trance-like. In 1966, ketamine was patented by Parke-Davis for use
as an anaesthetic in humans and other animals. In 1970, the United States Food
and Drug Administration (FDA) approved it for use in children and the elderly. By
the end of the 1970s, the FDA was worried about ketamine on the streets. In the
following years, ketamine has moved to the mainstream with the consolidation of
a dance culture, connected to rave parties, night clubs, and the underground scene
(10). Although ketamine is an anaesthetic, it can be a powerful stimulant at lower
doses, and it is usually used in combination with other drugs (see chapters 4 and
6). The album “Dig your own hole” (figure 1.2), by the electronic music duo The
Chemical Brothers, gives a good example of how the dance and drug cultures are
connected: its ninth track is entitled “Lost in the K-hole” (12); “K” is a common
nickname for ketamine, while the “K-hole” is a state of deep introspection, filled
with hallucinations, and even out-of-the body sensations, caused by ketamine.
13
IntroductionFigure 1.2: Cover of the classic electronic music album “Dig your own hole” by The Chemical Brothers (12).
Aims and outline of this thesis
This thesis aims to provide a wide analysis about the use of ketamine as a depression, PTSD and chronic pain medicine, from the users’ point of view to brand new scientific data. Furthermore, the exploration of the accidents and fatalities that recreational and medical uses of ketamine can cause is also an objective of this thesis.
Chapter 2 introduces the review article entitled “Oral ketamine for the treatment of pain and treatment-resistant depression”, published in the British Journal of Psychiatry (13). Appendices 1, 2 and 3 also contain information gathered by this study.
The third chapter presents the piece “Special features of special K: applications for pain and depression treatments”, referring to ketamine through another nickname: special K. It is published in the book “Breaking Convention: psychedelic pharmacology for the 21
stcentury”. The Breaking Convention is the largest and most relevant psychedelic science conference in Europe.
Following the need for more information regarding the consequences of ketamine use, chapter 4 presents the article “The use of ketamine to cope with depressive symptoms: a qualitative analysis of the discourses posted on a popular online forum”, where the qualitative method was applied in order to perform a
1
14
Chapter 1content analysis in the discourses of Bluelight members. Bluelight is an online drug forum, with precious information about self-medication with ketamine.
On chapter 5, “Ketamine as a new management tool for persistent physical and mental pain” discusses the development of central nervous system sensitisation (also known as “central sensitisation”) in the aggravation of chronic physical pain, its relationship to depression, and how ketamine can be useful to treat both.
Chapter 6 introduces a systematic review about overdoses and deaths connected not only to ketamine, but also to its analogues (e.g. phencyclidine and methoxetamine). “Overdoses and deaths related to the use of ketamine and its analogues: a systematic review” examines several cases reported in the scientific literature and brings a relevant discussion about the dangers of ketamine use, in medical and non-medical settings.
Lastly, chapter 7 provides a general discussion on the topic, including future
perspectives and recommendations for upcoming research.
15
IntroductionReferences
1. Sessa B. The ecstatic history of MDMA: from raving highs to saving lives. In: King D, Luke D, Sessa B, Adams C, Tollan A, editors. Neurotransmissions: essays on psychedelics from Breaking Convention. London: Strange Attractor Press; 2015. p. 89-101.
2. Hofmann A, Schultes RE, Rätsch C. Plants of the Gods: their sacred healing and hallucinogenic powers. Rochester: Healing Arts Press; 1996.
3. Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al.
Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 2018;235(2):399-408.
4. Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, et al. Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. British Journal of Psychiatry. 2012;200(3):238-44.
5. Griffiths RR, Johnson MW, Richards WA, Richards BD, Jesse R, Maclean KA, et al.
Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. Journal of Psychopharmacology.
2018;32(1):49-69.
6. Petri G, Expert P, Turkheimer F, Carhart-Harris R, Nutt D, Hellyer PJ, et al.
Homological scaffolds of brain functional networks. Journal of The Royal Society Interface. 2014;11(101):20140873.
7. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD). Journal of Psychopharmacology. 2013;27(1):40-52.
8. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology. 2011;25(4):439-52.
9. Wolfson P. Introduction to “The ketamine papers”. In: Wolfson P, Hartelius G, editors.
The ketamine papers: science, therapy, and transformation. Santa Cruz: Multidisciplinary Association for Psychedelic Studies; 2016. p. 1-23.
10. Jansen K. Ketamine: dreams and realities. Santa Cruz: Multidisciplinary Association for Psychedelic Studies; 2000.
11. Domino EF, Domino EF. Taming the ketamine tiger - 1965. Anesthesiology.
2010;113(3):678-84.
12. The Chemical Brothers. Dig your own hole. London: Orinoco Studios; 1997.
13. Schoevers RA, Chaves TV, Balukova SM, aan het Rot M, Kortekaas R. Oral ketamine for the treatment of pain and treatment-resistant depression. British Journal of Psychiatry.
2016;208(2):108-13.
1
Chapter 2
Oral ketamine for the treatment of pain and
treatment-resistant depression
By:
Robert A. Schoevers Tharcila Chaves Sonya M. Balukova
Marije aan het Rot Rudie Kortekaas
Published in the British Journal of Psychiatry (2016) 208: 108-113 doi: 10.1192/bjp.bp.115.165498
Supplementary content available in appendices 1, 2 and 3
18
Chapter 2Abstract
Background: Recent studies with intravenous application of ketamine show remarkable but short-term success in patients with major depressive disorder. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.
Aims: To review the literature about the dosing regimen, duration, effects, and side effects of oral, intravenous, intranasal, and subcutaneous routes of administration of ketamine for treatment-resistant depression (TRD) and pain.
Method: Searches in PubMed with the terms “oral ketamine”, “depression”, “chronic pain”, “neuropathic pain”, “intravenous ketamine”, “intranasal ketamine”, and
“subcutaneous ketamine” yielded 88 articles. We reviewed all papers information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results, and side effects, as well as study quality.
Results: Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for TRD in terms of tolerability and side effects.
Conclusions: Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer- term negative consequences. The short- and longer-term depression outcomes, as well as side effects, need to be studied with rigorous randomised controlled trials.
Declaration of interest: None.
19
Ketamine for the treatment of pain and treatment-resistant depression
Introduction
The rapid antidepressant action of the glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has kindled great interest and optimism among researchers, clinicians and patients (1,2). Both open-label studies and randomised controlled trials (RCTs) in treatment resistant unipolar or bipolar depression (TRD) have shown antidepressant effects occurring within hours of intravenous (IV) infusion with ketamine. This supports the idea that, besides the monoaminergic systems, the glutamatergic system may also be targeted for the treatment of major depressive disorder (MDD) (3). In patients with mood disorders, glutamate levels in serum and cerebrospinal fluid are altered (4). Ketamine increases the presynaptic release of glutamate, resulting in higher extracellular levels of glutamate by a combination of disinhibition of the neurotransmitter γ-aminobutyric acid (GABA) and blockage of the NMDA receptors at the phencyclidine binding site within the ion channel (5). This increase in extracellular glutamate release favours coexpressed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), resulting in “an increased glutamatergic throughput of AMPA relative to NMDA”
(5). The glutamatergic system is also fundamental for neuroplasticity, which is linked to mood disorders (6). NMDA receptor activation is part of the induction process for long-term potentiation, an important form of synaptic plasticity. Synapse- associated proteins and the number of dendritic spines then increase, for example, in the prefrontal cortex (7), thus reversing the structural and functional deficits resulting from long-term stress exposure (8).
In TRD studies, ketamine has mostly been administered intravenously (9). A rapid IV infusion of ketamine for TRD, usually at a dose of 0.5 mg/kg, leads to an immediate bioavailability of 100%. To date, six double-blind crossover RCTs have been published that compared a single dose of IV ketamine to placebo: five of them used an inactive placebo – saline (2,10-13) – and one used an active placebo – midazolam (14). Overall, these studies showed rapid initial effects (40 minutes after infusion) that increase to one day post-infusion, but overall the difference between ketamine and placebo (inactive or active) was no longer statistically significant at seven days post-infusion. A recent open-label study that compared ketamine with active placebo (midazolam) had a similar effect size of 0.81 at one day post-infusion, but again the effect did not last (15). The great challenge with ketamine as an antidepressant is to extend its duration of action.
To study the efficacy of repeated ketamine infusions, a non-blinded study provided six infusions over two weeks. After the last infusion eight of nine patients (89%) were in remission. The average time to relapse after the last infusion was
2
20
Chapter 2much longer than in single injection studies: nineteen days (SD=13) after the last infusion (16). Investigators reported no worsening of cognitive function during the follow-up period although this was not formally tested.
Other researchers (17,18) have sought to maintain the effect of IV ketamine by adding oral riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, but this was unsuccessful. Future research should then explore new strategies to optimise the antidepressant response, including dosing regimens and routes of administration (9).
To date, the field of psychiatry has paid little attention to the experience with oral and other non-IV administrations of ketamine for chronic pain. Ketamine is a well- known anaesthetic, with analgesic effects that may be used to treat chronic pain in a range of disorders (19). In the field of pain management, there is ample experience with the oral, as well as IV application of ketamine. Indications for oral ketamine include neuropathic pain of various origins, complex regional pain syndrome, cancer pain, orofacial pain, and phantom limb pain. As in depression, the therapeutic effect is believed to be based on antagonism of the NMDA receptor (20).
This review describes the findings of these studies and combines the fields of pain management and depression, with special attention to safety, dosing regimen and treatment duration.
Method
We searched PubMed with the following terms: [“oral ketamine” AND “depression”], [“oral ketamine” AND (“chronic pain” OR “neuropathic pain”)], [“intravenous ketamine” AND “depression”], [“intravenous ketamine” AND (“chronic pain”
OR “neuropathic pain”)], [“intranasal ketamine” AND “depression”], [“intranasal ketamine” AND (“chronic pain” OR “neuropathic pain”)], [“subcutaneous ketamine”
AND “depression”] and [“subcutaneous ketamine” AND (“chronic pain” OR
“neuropathic pain”)]. The final search date was 27 October 2014. Our searches
yielded 112 studies. We excluded literature reviews, studies with animals and studies
with healthy individuals, thereby yielding 88 studies. We scanned all papers for
information about study type and size, dosing regimen, number of individuals who
received ketamine, number of ketamine days per study, results and side effects. When
these were described, we entered them into two tables: table 1 refers to the studies
where ketamine was used to treat depression (appendix 1) and table 2 refers to the
studies where ketamine was used to treat pain (appendix 2). We designed two graphs
with the information provided by those tables (figures 2.1 and 2.2).
21
Ketamine for the treatment of pain and treatment-resistant depression
In total, for depression, four studies were found using oral ketamine (n=22), 43 studies used IV ketamine (n=763), two studies used intranasal ketamine (n=19), one study used sublingual ketamine (n=26), and two case reports concerned intramuscular (IM) ketamine (n=3). For pain, twelve studies used oral (n=76), 21 studies IV (n=553), two studies intranasal (n=21), and one study IM ketamine (n=35). We found only one study on subcutaneous ketamine for pain that met the inclusion criteria, but it presented insufficient data (no dose and no number of ketamine days described), so we excluded it from the analysis. We found no subcutaneous ketamine for depression study. One sublingual ketamine for depression study and three IM ketamine studies (one for pain and two for depression) were included in our analysis.
To compare dosing regimens across studies, we calculated the daily oral racemate equivalent dose (DORED), in mg/kg/day, by multiplying the IV dose by five to correct for the five times lower average oral bioavailability (21,22) and by multiplying the S-ketamine dose by two to correct for the double potency relative to racemate.
For intranasal dosing regimens, we obtained the DORED by multiplying them by 2.25 to correct for the 2.25 times lower oral bioavailability (23). In the case of IM dosing regimens, we calculated the DORED by multiplying them by 4.65 to correct for the 4.65 times lower oral bioavailability (22). We multiplied the sublingual dose by 1.5 to obtain their DORED (23).
Results
Oral ketamine for depression
Five uncontrolled open-label studies were found that investigated the antidepressant properties of oral (including sublingual) ketamine (24-28). A small study (n=4) found depression relief in patients with TRD who were given up to 1.25 mg/kg oral S-ketamine for two weeks (24). In one study on palliative healthcare (25), the effects of ketamine on pain, anxiety and depression were assessed. This case report describes a hospice patient who was treated daily with 40 mg oral ketamine, which relieved all three complaints. Another hospice-based study described two severely ill and depressed patients who showed significant improvements lasting one or two weeks after a single oral dose of 0.5 mg/kg ketamine (27). A more recent hospice- based study administered daily oral ketamine (0.5 mg/kg) over a 28-day period to patients in hospice care who had depressive symptoms. Eight out of fourteen patients completed the trial and showed significant improvement in pain and depression with few side effects (26). De Gioannis and de Leo (2014) treated two patients with chronic suicidal ideation (and at least two significant past suicide attempts) with a
2
22
Chapter 2solution of ketamine ingested with a flavoured drink. The maximum dose used was 3 mg/kg of ketamine. Both patients achieved sustained remission from suicidal ideation (28).
Lara et al. (2013) reported on 10 mg sublingual ketamine, administered once, or every two, three or seven days for a total of up to twenty doses. They observed improved mood in 20 out of 26 patients with TRD. The antidepressant effects outlasted the acute side effects, which primarily concerned light-headedness, and did not include euphoria or dissociation (29).
Clearly, these are only first indications of possible antidepressant effects of oral ketamine, as all of these studies were very small and uncontrolled, and the quality of the evidence was low.
Dosing regimen and treatment duration of ketamine in chronic pain Figures 2.1 and 2.2 show that both for depression and pain most studies used the IV route of application. Expressed in DORED, the doses for depression are in the lower range compared with studies that investigated analgesic use. Also, the graphs show that ketamine as an antidepressant is generally given for shorter durations (1 to 32 days) than ketamine as an analgesic. Finally, it shows that on average IV ketamine is given for a shorter duration than oral ketamine. Studies with oral ketamine, where pain was the primary indication, administered ketamine once (30) or for as long as 660 days (31), with most studies in the range of 20 to 80 days.
The doses used in the analysed pain studies differed from 0.1 DORED via
oral administration (30) to 62.5 mg/kg/day intravenously (32). It is not possible
to establish a dose-response association, but the majority of the analysed pain
studies describe ketamine as effective in reducing pain, even in low oral doses. The
exceptions are six studies that used IV ketamine (33-38), which did not lead to any
reduction in the pain scores. Although the study conducted by Kapural et al. (2010)
used a high dose (DORED of 21.5 mg/kg/day), it did not achieve an improvement
in long-term pain scores in patients with high opioid requirements (33).
23
Ketamine for the treatment of pain and treatment-resistant depression
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1516171819 20
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29 303132 3334
353637
38 39404142 43
44 45 46
47 85 83 84
1 234
86 87
-10
-50
510
15
20
25
30
35
40 -505101520253035
DORE D (m g/kg /da y)
Number of ketamine days
Ket am in e fo r d ep res sio n
intravenous antidepressant sublingual antidepressant intranasal antidepressant oral antidepressant intramuscular antidepressant Figure 2.1: Overview of daily dose of ketamine for treating depression and number of ketamine days. Fifty-two studies about ketamine used to treat depression were included. The x-axis represents the number of ketamine days, which is different from the study duration (in some studies, only one or few doses were given during a long follow-up time) The size of the bubbles represents the sample size (number of individuals who received ketamine). The numbers close to the bubbles refer to the study identification, which can be found in table 1 (appendix 1).2
24
Chapter 26061
62 63 6465
666768 69
70 71
72 73 747576
77
78
79 80 88 48495051525354 55565758 598182 -20
-10
010
20
30
40
50
60
70 1101001000
DORE D (m g/kg /da y)
Number of ketamine days
Ket am in e fo r p ai n
intravenous analgesic intramuscular analgesic oral analgesic intranasal analgesic Figure 2.2: Overview of daily dose of ketamine for treating pain and number of ketamine days. Thirty-six studies about ketamine used for treating pain were included. The x-axis represents the number of ketamine days, which is different from the study duration (in some studies, only one or few doses were given during a long follow-up time). The size of the bubbles represents the sample size (number of individuals who received ketamine). The numbers close to the bubbles refer to the study identification, which can be found in table 2 (appendix 2).25
Ketamine for the treatment of pain and treatment-resistant depression
Some studies in patients with chronic pain (that could be progressive and/or related to terminal illness) showed that patients required higher doses over time. For instance, Villanueva-Perez et al. (2007) administered 30 mg of oral ketamine every eight hours to a patient with complex regional pain syndrome type 1, increasing this dose weekly in 5 mg until a maximum dose of 60 mg/6 hours was reached. This patient kept this last dose for more than two years with significant improvement mainly in the first seventeen months (31). Vick and Lamer (2001) achieved significant improvement in pain, allodynia and hyperalgesia in one patient with central post- stroke pain at the dose of 50 mg oral ketamine three times per day. This treatment lasted three months (39). This is in line with preclinical and clinical studies on anaesthesia and studies on ketamine misuse, that suggest that tolerance may develop (40-45).
Clearly, the dosage is directly related to the bioavailability of ketamine. With oral administration, the bioavailability is generally low, because of extensive first-pass metabolism (22). Reported values of oral ketamine in adults are in the range of 17 to 24% (21-23,46). A study by Brunette et al. (2011) in children showed the highest bioavailability (45%), and used a nasogastric tube and a 10 mL water flush (47), but Yanagihara et al. (2003) also used a water flush (100 mL) and found a bioavailability of only 20% in adults (23). Other factors underlying the variability after oral dosing may include the formulation (tablet or solution, ketamine concentration), state of the stomach, dietary enzyme induction, and individual differences in cytochrome phenotype. It should be noted that interindividual pharmacokinetic variability is common to oral administration in general (48-50) and has also been described for currently prescribed antidepressants (51). Intranasal and sublingual ketamine administration have been reported to yield 45% and 30% bioavailability, respectively (23), but interindividual variability has been described for these routes of ketamine administration as well (52,53). Ketamine absorption after IM injection has been described as more rapid, with a bioavailability of 93% (22).
Safety and abuse potential
The most common side effects of IV ketamine are psychotomimetic effects and dissociative symptoms (54,55), which correlate with high initial plasma levels and may thus be less pronounced in oral administration (56). Feeling “high” after ketamine is also dependent on plasma levels (56). Other known side-effects are confusion, dizziness, euphoria, elevated blood pressure and increased libido, although all of these usually dissipate within two hours of IV infusion (57).
Ketamine neurotoxicity has been described in preclinical studies (58), but this was suggested to be due to the presence of the preservative chlorobutanol rather than
2
26
Chapter 2to the ketamine itself (59). Without preservative, ketamine can induce neurotoxicity when injected in very high doses into the subarachnoid space (60). The study of Sun et al. (2014) showed that IV ketamine given to adolescent cynomolgus monkeys at a dose of 1 mg/kg in saline for six months might also produce permanent and irreversible deficits in brain function through the neurotoxic effect caused by the activation of apoptotic pathway in the prefrontal cortex (61). This appears to be in contrast with studies in humans where ketamine was given in similar or higher doses with few mentions of cognitive problems (10,11). It should be noted that currently available clinical studies with IV ketamine used only one or few applications. In the studies involving pain, patients were given ketamine more often, but mostly did not have the “peak effect” of IV application. Prolonged ketamine misuse has been associated with white matter changes (62), memory changes (63), neurocognitive impairment (55,64), and reduced well-being (55). Finally, inflammation and damage to the ureters and bladder are well documented in very heavy ketamine users who consume daily amounts of one gramme by inhalation and for prolonged periods of months or even years (65,66). Notably, in these studies, daily doses were substantially higher than those used in clinical studies. Calculated in DORED, these users had approximately 80 mg/kg/day, which is 2.2 times higher than the highest DORED found in a study where ketamine was used to treat depression (67).
The majority of the pain and depression studies retrieved by our search did not report the side effects of oral ketamine as a major burden in treatment maintenance.
Side effects commonly mentioned were dizziness, hallucinations, nausea, vomiting, drowsiness, confusion, light-headedness, headache, somnolence, and anxiety. An exception to this is the study by Kannan et al. (2002) involving nine patients with neuropathic pain, which stated that the beneficial effects in the management of intractable neuropathic pain were limited in some patients by the adverse effects such as nausea, vomiting, loss of appetite, drowsiness, sedation, and feeling of unreality (68). Haines and Gaines (1999) found that ketamine caused an analgesic response in only 14% of individuals and described that the adverse events (light-headedness, dizziness, tiredness, headache, nervous floating feeling, and bad dreams) limited the use of ketamine in almost half of their patients (69). Hallucinations and paranoid feelings were reported in only one patient (31); memory impairment and dysuria were reported in one study on twelve patients (70).
Very low dose sublingual administration of 10 mg (approximately equivalent
to 0.036 mg/kg IV) was not associated with euphoria or psychotic and dissociative
symptoms (29). In some studies, increased blood pressure was controlled with the
concomitant administration of a benzodiazepine (71,72). The reported adverse
events were usually limited to the ketamine treatment phase and did not persist after
27
Ketamine for the treatment of pain and treatment-resistant depression
ketamine discontinuation (see tables 1 and 2 in appendices 1 and 2, respectively, for more details about side effects per study).
Another concern with ketamine is its misuse potential, which has been demonstrated in both animals and humans (73,74). Ketamine has been used as a street drug since the 1960’s, probably because of its rapid effects, its low cost and its specific psychotropic effects such as hallucinatory and dissociative experiences (e.g.
“melting into the surrounding”, “out-of-body” experiences), as well as “giggliness”
(75,76). Multi-drug users who have used ketamine in large doses recreationally have also expressed concerns about its addictive properties (75). No studies have compared different routes of ketamine administration directly, but the misuse potential is generally found to be higher with IV administration or inhalation that produces much more rapid and intensive effects compared to oral administration (77). In line with this, the psychedelic effects of ketamine are directly related to plasma concentrations (56). Importantly, in the pain studies mentioned earlier, addiction or misuse were not described as side effects. Still, it is clear that these unwanted effects should be balanced against the possible beneficial properties of ketamine.
Discussion
Overall, the results suggest that oral ketamine in the described doses may be well tolerated. However, few studies have systematically studied its possible longer-term consequences. In comparison with studies of patients with pain, treatment duration in the currently available studies of depression is at the lower end of the spectrum.
Further research is needed including basic science, acceptability and feasibility studies, ethical perspectives, and ultimately building to randomised trials designs.
A number of issues need to be addressed. First, ketamine raises concerns, such as its potential for misuse, that warrant solid monitoring. Even though our review did not show such problems to be very important in studies on depression and pain, this may be much more of a problem if ketamine were to be used on a broader basis in clinical practice. We agree with the statement made by Caddy et al. (2015), in a Cochrane review about ketamine for depression in adults, that there is a need for studies examining the longer-term effects of repeated use of ketamine that also take into account oral and IM routes (78).
Second, even though the side effect profile of oral ketamine seems to be milder than that reported in IV studies and in severe drug misusers, the overall safety profile would warrant that ketamine should be provided in a hospital setting. After an initial inpatient phase, oral ketamine might, however, be prescribed to depressed
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Chapter 2patients outside the hospital environment for maintenance purposes, depending on an assessment of risk for each individual patient. Furthermore, side effects should systematically be monitored using an instrument, such as the SAFTEE, the
“systematic assessment for treatment emergent events” (79).
Third, oral bioavailability of ketamine is rather low and variable; studies should take into account blood levels of active metabolites and ketamine formulation. Fourth, as the antidepressant effects of ketamine may partially be related to its anaesthetic potential, especially in depressed patients with pain, a thorough assessment of both depressive symptoms and pain needs to be incorporated into upcoming trials.
Based on the above, we believe it is time to conduct rigorous RCTs that determine the benefits, as well as possible unsolicited consequences of oral ketamine, given for weeks rather than days, for patients with TRD.
Acknowledgements
The authors are grateful to Robert Berman and Lisa Roach of Yale University School
of Medicine for help with data mining.
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Ketamine for the treatment of pain and treatment-resistant depression
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