ARTICLE DOI: 10.31480/2330-4871/062

RESEARCH ARTICLE OPEN ACCESS

Ketamine: Old Drug but New Use for Neuropathic Pain

Zac Hana, Suha Abdulla, Azeem Alam and Daqing Ma

Anesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Campus, London, UK

*Corresponding author: Professor Daqing Ma, BOC Chair, Anesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Campus, London, UK, Tel: +44(0)20-3315-8495, E-mail: d.ma@imperial.ac.uk

Editor: Yuan-Xiang Tao, Ph.D., M.D., Professor and Vice Chair, Director, Center for Pain Medicine Research Department of Anesthesiology, Editor in Chief, The Translational Perioperative and Pain Medicine, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 S. Orange Ave., MSB, E-661 Newark, NJ 07103. Phone: 973-972-9812 (O), Email: yt211@njms.rutgers.edu

Received: December 15, 2017 | Accepted: January 13, 2018 | Published: January 15, 2018

Citation: Hana Z, Abdulla S, Alam A, Ma D. Ketamine: Old Drug but New Use for Neuropathic Pain. Transl Perioper & Pain Med 2018; 5 (1):1-13.


Abstract


Neuropathic pain is a debilitating form of chronic pain that affects 6.9-10% of the population. Health-related quality-of-life is impeded by neuropathic pain, which not only includes physical impairment, but the mental wellbeing of the patient is also hindered. A reduction in both physical and mental wellbeing bares economic costs that need to be accounted for. A variety of medications are in use for the treatment of neuropathic pain, such as calcium channel α2δ agonists, serotonin/noradrenaline reuptake inhibitors and tricyclic antidepressants. However, recent studies have indicated a lack of efficacy regarding the aforementioned medication. There is increasing clinical and pre-clinical evidence that can point to the use of ketamine, an "old" anaesthetic, in the management of neuropathic pain. Conversely, to see ketamine being used in neuropathic pain, there needs to be more conclusive evidence exploring the long-term effects of sub-anesthetic ketamine.

Keywords


Ketamine, Neuropathic pain (NP), Clinical, Pre-clinical, Treatment

Introduction


The International Association for the Study of Pain (IASP) introduced a new definition for neuropathic pain (NP) in 2011, in which NP was and is described as "pain caused by a lesion or disease of the somato sensory system" [1]. The cause for a dysfunctional somatosensory system, and consequentially NP, can be classified into either an anatomical or etiological source. Furthermore, the symptoms associated with NP are separated into either spontaneous pain or stimulus-evoked pain [2]. Spontaneous pain is a common form of abnormal pain that occurs independently from any stimuli, and is composed of three components: paresthesia, paroxysmal, and superficial. Conversely, stimulus-evoked pain requires an external stimuli to induce a pain sensation, and is further categorized into the type of response that a patient elicits: either positive-symptoms or negative-symptoms. Positive-symptoms are comprised of allodynia and hyperalgesia, which are reflective of disproportionate neuronal activity and hyperexcitability. Allodynia can be triggered by a usually non-painful stimulus, whereas hyperalgesia is an increased pain response when evoked by nociceptive stimuli.

NP pain is usually debilitating, and due to its chronic and distressing nature it also has a negative impact on the patient's health-related quality-of-life (HRQoL). A review analysing 52 studies in patients with 6 different disease-causing NP determined that NP was associated with greater impairments in a number of HRQoL domains. The extent of impact is also dependent on the different measures of HRQoL that were utilized in each study, considering that each measure may have a different sensitivity to the effects of NP [3]. Overall, NP is associated with higher pain severity and greater interference on daily activities [3-11]. NP has economic consequences, in the form of direct NP pain costs and indirectly through impairment on quality of life, which encompasses restricted employability. In the UK, patients with post-herpetic neuralgia (PNH) and who were also attending a tertiary referral center had a lifetime cost of £770. Comparatively, a 1-year incidence cohort would differ between an overall lifetime cost of £4.8 million (incidence of 21,000 people) to £17.9 million (incidence of 78,200 people) [12].

Tricyclic antidepressants, calcium channel α2δ agonists and serotonin/noradrenaline reuptake inhibitors are the first-line treatment for NP. Unfortunately, treatment for NP pain has been inconsistent, whereby inadequate targeting of the underlying mechanism behind NP has resulted in poor pain relief in two-thirds of patients [13,14]. There is increasing pre-clinical and clinical evidence to indicate the efficacy of sub-anesthetic doses of ketamine in NP, although ketamine has been used with caution and subsequent preclusion from clinical application due to its psychotomimetic effects [15]. The intention of this review is to analyze the current body of animal model studies and clinical trials pertaining to ketamine, and to see if ketamine has a place in the treatment of NP.

Epidemiology


Questionnaires

For decades, the epidemiology of NP was understudied. This is because there were no real valid or reliable clinical instruments that could appropriately identify the various classifications of NP. Over time, researchers began developing questionnaires that had good discriminative properties for the identification of NP, such as the Douleur Neuropathique en 4 Questions (DN4) questionnaire [16]. Other tools include: The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and its self-report counterpart (S-LANSS); The Neuropathic Pain Questionnaire; pain DETECT; ID Pain; Neuropathic Pain Scale; and Brief Pain Inventory [17].

Neuropathic pain in the general population

An extensive systematic review of epidemiological studies of NP in the general population was carried out between January 1966 to December 2012 [18]. Although data from specialist clinics, pain clinics, and studies focusing on population subgroups were excluded, the study categorized their results into patients with chronic pain and neuropathic characteristics and NP as associated with a specific condition. The underlying causes for NP are predominately herpes-zoster, diabetes, leprosy, cancer, infection by human immunodeficiency virus, carpal tunnel syndrome and trigeminal neuralgia. For each clinical condition, NP presents a different prevalence and incidence. For instance, the following conditions and their associated person-years (PY): post-herpetic neuralgia (3.9-42.0/100,000 PY) [19-22], trigeminal neuralgia (12.6-28.9/100,000 PY) [19,21,22], pain diabetic peripheral neuropathy (15.3-72.3/100,000 PY) [19,21,22] and glossopharyngeal neuralgia (0.2-0.4/100,000 PY) [22,23]. The use of rates per person-years throughout these studies is not clinically useful, as the PY is not a productive indicator of how many cases are to occur in a particular time or population. Interestingly, prevalence estimates of specific causes of NP are usually lower (1-2%) than reports on classic symptoms (6-8%) [24]. Ultimately, it has been considered that the best prevalence estimate of NP is 6.9%-10% [18]. It was also proposed that the discrepancy in prevalence of NP was due to the heterogeneity in the ascertainment tools that were used. Studies that used DN4 and S-LANSS had wider prevalence estimation (3.3-17.9%) than tailored and validated ascertainment tools (6.9-10%).

A French study identified higher prevalence of chronic pain with neuropathic features in the middle age (50-64 years), manual professions and those living in rural areas. Furthermore, the pain was associated with the lower limbs more so than any other part of the body [16]. In Germany, researchers interviewed participants by telephone, whereby 18.4% had non-NP chronic pain and 6.5% had NP [25]. The study highlighted that patients with NP were more likely to have higher pain severity, interference in daily activities due to pain compared to non-NP patients, and higher rates of co-morbidities including major depressive disorder. In the UK, patients at six family practices in Aberdeen, Leeds, and London were deemed to have a NP prevalence of 8%. Patients with NP tend to be female, slightly older, no longer married, had reduced socioeconomic levels, and the pain was more severe and longer in duration than non-NP pain [26]. In Austria, the prevalence of NP was 3.3%, with prevalence increasing to 26% in 41-50 year-olds, and 24% in 51-60 year-olds [8]. Higher rates of prevalence of NP were found in Canadian participants, in which 17.9% had NP symptoms. Once again, features of being female, economically disadvantaged, a more severe form of pain compared to non-NP, and restrictions of daily activities were reported [27].

Molecular Mechanisms of Neuropathic Pain


Multiple pathophysiological mechanisms underpin NP. Moving away from an etiology-focus to a mechanism-based approach may prove to be clinically important for improving the efficacy of the treatment options that could be available.

Peripheral sensitization

As a consequence of nerve damage, ongoing spontaneous activity and excessive electrophysiological excitability occur in the following sites: cell body of the damaged neuron in the dorsal root ganglia; the neuroma; and finally, the neighbouring functioning afferents. In other words, nociceptive primary afferents become hyperactive because of nerve damage, which is defined as peripheral sensitization [28,29].

Voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 undergo differential expression due to nerve damage [30]. Marked changes to the voltage-gated sodium channels result in lower thresholds and an increased rate of firing [31]. Studies investigating the two inherited-pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, have reported gain-of-function mutations in the gene responsible for Nav1.7, SCN9A. Conversely, insensitivity to pain occurs when there is a loss-of-function in these sodium channels [32]. Potassium channels are also believed to play a part in NP, since peripheral nerve injury is believed to cause a reduction in potassium channel expression [33].

An inflammatory response, consisting of cytokinesIL-1β, IL-6, and tumour necrosis factor (TNF) are believed to participate in peripheral sensitization [34-37]. IL-1β is considered to exert its NP effects through a signaling cascade and secondary production of prostaglandins, bradykinin or nitric oxide. In addition, IL-1β can act directly on sensory neurons, increasing its sensitivity through a IL-1R1/TyrK/PKC mechanism [34,38]. The complex IL-6/sIL-6R, which is composed of IL-6 and its soluble receptor form, sIL-6R, promotes increased sensitivity for noxious heat through a gp130/Jak/PKC mechanism [34,38]. Finally, TNF-stimulation of TNF-receptor 1 and TNF-receptor 2 is associated with an activation of calcium mobilization and protein kinases in neurones [38,39].

Transient receptor potential channels (TRP) are a family of channels that are expressed on sensory nerves, whereby they respond to stimuli differently. Spinal nerve injury had resulted in greater levels of TRPML3 in the undamaged dorsal root ganglion in comparison to the control [40]. Gene transcription is modulated through a cAMP-dependent PKA and Ca2+/phospholipid-dependent PKC complex signalling mechanism, as nerve damage can disrupt the flow of signal substances from the nerves to the dorsal root ganglion cell body [41]. There is also the promotion of proteins ERK, p-38, and c-jun, which cause neuronal degeneration and the preservation of pain sensation [42-44].

Central sensitization

The neurones in the dorsal horn can undergo increased sensitivity in response to peripheral nerve injury. This is characterised by increased neuronal activity, an expansion of receptive fields and a spreading of spinal hyperexcitability to other sections. The central nervous system's modulation in response to peripheral nerve damage is due to a sophisticated cascade system. The sensitized C-fibres release glutamate which act on N-methyl-D-aspartate (NMDA) receptors and neuropeptide substance P on the dorsal horn neurons. Primary dorsal horn neurons interact with second-order dorsal horn neurons, since after peripheral nerve injury these neurons express abnormal Nav1.3 [45]. Central voltage-gated N-calcium channels at presynaptic sites of primary afferents are overexpressed after peripheral nerve damage, causing increased glutamate and substance P release [46,47]. In addition, mitogen-activated protein kinase system (MAPK) is an intracellular cascade that is involved in central sensitization [48]. As central sensitization takes hold, non-painful stimuli can stimulate Aδ and Aβ mechanoreceptors, triggering a painful response. Interneurons release γ-aminobutyric acid (GABA), which inhibit dorsal horn neurons. In nerve damage, there is a loss of GABA-releasing neurons, causing a reduction in inhibition [49].

Microglia and NP

A recent published review by Zhao, et al. documented the role of microglia in the pathobiology of neuropathic pain development [50]. The underlying mechanism is the release of various mediators from injured neurons including, but not limited to, Neuregulin-1, matrix metalloproteinase (MMP)-2, MMP-9, chemokine (C-C motif) ligand 2 (CCL2) and fractalkine. These mediators decrease inhibitory interneurons whilst increasing excitatory currents and the recruitment of microglial cells. Microglia release factors and cytokines, such as interleukin IL-6, IL-1β and TNF-α, that contribute to pain facilitation.

Pharmacology of Ketamine


Chemistry

Ketamine is a phenylpiperidine analogue structurally consisting of 2(2-chlorophenyl)-2-(methylamino) cyclohexanone (C13H16ClNO). It has a molecular weight of 237.727 g/mol. As well as being freely soluble in water, it is highly lipophilic [51].

It exists as two stereoisomeric forms being Esketamine [S(+)] and Arketamine [R(-)], together known as the racemic mixture, with a pKa of 7.5 and acidic pH between 3.5-5.5 [52]. Whilst the former has a greater analgesic and anesthetic potency, with studies suggesting a two to four time increase in efficacy [53,54], the enantiomers' pharmacokinetic profiles are similar. This drug is available commercially in either the form of the racemic mixture named Ketalar or the S(+) enantiomer being Ketanest-S or S-Ketamine.

Routes of administration

Clinical consideration of the route of administration is vital in preventing extensive first-pass metabolism, resulting in sub-optimal concentration of the drug in the plasma [55]. Ketamine is traditionally administered as a bolus either intravenously or through intramuscular route [56], of which the highest percentages of bioavailability are achieved at 100% and 93% respectively.

Despite this, studies have shown that it remains effective in its analgesic capacity in treating NP by rectal, transdermal, oral, sublingual and subcutaneous routes [57]. Inhalation of nebulized ketamine has recently been shown to allow rapid assimilation of the drug without the need for invasive measures in emergencies [58,59].

Pharmacokinetics

Distribution

Ketamine displays a rapid onset of acute analgesic action in NP with an alpha half-life of 11 minutes. Its lipophilic properties allow it to readily pass the blood-brain barrier, achieving a blood-effect site equilibration half-life between 1-10 minutes [53]. After IV administration, its volume of distribution is 1-3 L/kg with a re-distribution half-life of 7-15 minutes [60,61].

In relation to the long-term therapeutic use of ketamine in NP, studies have successfully shown that the onset and offset of ketamine are slower, with patients experiencing analgesic benefits up to 50 days after treatment was stopped [62]. In a study conducted by Sigtermans, et al., patients with Complex Regional Pain Syndrome Type 1 (CRPS-1), a condition characterized by chronic pain that is resistant to conventional therapy, were treated with a personalized stepwise dosage of 20-30 mg/hour of S-Ketamine over 4.2 days [63]. It was subsequently found ketamine's half-life was 11 days. As such, it is hypothesized that ketamine triggers a desensitization of NMDAR restoring nociceptive homeostasis [64]. The clinical benefit of significant pain relief persists, but is slowly abated when ketamine is completely cleared by the body.

Metabolism and elimination

Ketamine is N-demethylated by the hepatic cytochrome P450 enzymes. The main isoenzyme responsible for this reaction is CYP3A4, with minor support from CYP2B6 and CYP2C9, to produce its major metabolite: norketamine [65]. This occurs within minutes after its administration through the intravenous route. As such, studies have shown that the concentration of norketamine has been found to exceed ketamine in cases where long-term bolus infusions were given [66]. Norketamine's concentration remains elevated above ketamine, acting as a non-competitive antagonist of the NMDA receptor (NMDAR). Studies are currently underway to establish the clinical implications of norketamine in anesthesiology, with preliminary findings suggesting it perpetuates algesic effects, negatively counteracting ketamine's action [66,67]. This contrasts with Goldberg, et al. who found that norketamine contributes to ketamine's analgesic effect [68]. More studies are required to elucidate the effect of norketamine on ketamine's clinical efficacy.

Elimination occurs when norketamine is subsequently further broken down into 4-, 5- and 6-hydroxynorketamine by the hydroxylation of its cyclohexane ring [69]. It subsequently undergoes glucuronidation in the liver and cleared through the kidney and bile. Studies have shown its clearance rate is 15 ml/kg/min and eliminated in 2.5 hours [70]. Following IV administration of ketamine, 91% is excreted in urine and 1-3% in faeces.

Mechanism of action

Ketamine is an uncompetitive antagonist of the ionotropic glutamatergic NMDAR receptor. This excitatory receptor is ubiquitously distributed in the brain and spinal cord, with those located in the dorsal horn of the spinal cord critically involved in nociception and allodynia [70,71]. Studies are increasingly implicating NMDAR in the induction and maintenance of central and peripheral sensitization to NP, known as the wind-up phenomena [72-74].

Ketamine exerts its strong analgesic action in NP through an extensive number of mechanisms, mainly through inhibition of NMDAR and reducing calcium-mediated neuronal death. Acutely, this prevents the afferent transmission of nociceptive signals [75]. In the long term, therapeutic administration of ketamine is believed to abate the up-regulation of the NMDAR in the dorsal horn of the spinal cord, therefore reducing the hypersensitivity of these nerves and pain perception [76,77]. As such, restoration of nociceptive homeostasis is achieved. In addition to this mechanism, Swartjes, et al. showed that ketamine stimulates the innate repair receptor (IRR) that is crucial for tissue repair and anti-inflammation in nerve damage [78]. Lastly, ketamine activates descending inhibitory, 'top-down', pathways to induce analgesia.

In addition to NMDAR, ketamine acts as an agonist to a series of receptors with the opioid receptor being the most relevant to NP. Stimulation of this receptor with the over-consumption of opioids leads to hyperalgesia, through common intracellular pathways shared with NP development [79,80]. Opioid-induced hyperalgesia is a paradoxical phenomenon in that increasing doses increases pain perception, which is mediated by opioids' pharmacokinetic profile as an NDMA agonist [81-83]. Therapeutically, numerous studies have shown that this can be counter-acted by the pharmacological inhibition of the NMDAR, with ketamine proving the most effective. Low-dose ketamine as an adjuvant significantly reduces pain scores, as well as the consumption of opioids [84,85], compared to when given opioids are administered alone [86-88].

Considerations: safety, tolerability and dosages

Ketamine use is associated with a vast array of side effects affecting mainly the cardiovascular, hepatic and nervous system [70]. A retrospective 5-year study conducted by Marchetti, et al. found that half of the patients with NP experienced side effects, with eight out of the fifty-five patients having to stop treatment [89]. It is vital comprehensive histories are taken from patients to screen out those who may be at a heightened risk of experiencing side effects.

Ketamine predominately affects the CNS, impacting both psychological and neurological functions. The most concerning of which are psychedelic symptoms occurring at an incidence of 5-30%, with recent research showing it activates reward regions in the brain including the hippocampus [90]. Liu, et al. have further implicated the dopamine system in ketamine's stimulatory effects, achieved through the cortex-striatum circuitry [91].

Neurobehavioural changes become apparent in patients, where they exhibit a myriad of sensations including but not limited to hallucinations, psychosis, anxiety, paranoia, schizophrenia-like state and frank delirium [92-94]. They may also experience intense euphoria, dissociation and depersonalization affecting their perception of visual, auditory and pain stimuli [95], as well as the essence of time [96]. Consequently, ketamine is a target for recreational abuse [97]. This stimulant effect is particularly achieved at low-doses, posing concerns for patients receiving subanesthetic doses for NP. However, in clinical practice this hallucinogenic and hypnotic effect can be attenuated with the use of benzodiazepines as co-adjuvants.

Cognitive deficits are an area of concern in the long-term administration of ketamine [98], with various studies indicating it negatively modulates genomic expression in the hippocampus. Mouse studies by Ding, et al. [99] found that GluA1, p-S845 and p-S831 expression necessary for the functional integrity of AMPA receptors in the hippocampus are compromised. This manifested in learning and memory deficits that were largely time and dose-dependent. Morgan, et al. further supports this notion, where frequent Ketamine users, out of a cohort size of 150, had reduced performances in spatial working memory and pattern recognition [100]. They found the frequency of usage positively correlates with a higher incidence of dissociative and delusional symptoms.

In addition to this, ketamine increases cerebral metabolism, cerebral blood flow (CBF), and intracranial pressure (ICP). Administration is thus contraindicated in patients who have or are at risk of intracranial pressure as ketamine may inadvertently increase this [101].

As a sympathomimetic, ketamine stimulates the cardiovascular system through the release of catecholamines whilst acting as a negative inotrope. This presents a significant problem in clinics as myocardial depression can occur either through high doses, or through prolonged durations of infusion. This particularly affects those with a history of cardiac disease, as when administered acutely, ketamine triggers tachycardia, increased blood pressure both systemically and pulmonary, as well as induces increased myocardial oxygen consumption [102]. Screening of patients and their monitoring is thus essential in ensuring safe administration of ketamine.

The hepatic system is affected to a lesser degree with patients exposed to repetitive or prolonged infusions of low-dose ketamine exhibiting elevated liver enzyme profiles [70,102-104]. A study conducted by Noppers, et al., where patients with CRPS-1 were treated with 100 hours of subanesthetic doses of ketamine, found an elevation that was extremely profound, terminating the study out of concerns for patient safety [102]. Liver biopsies have shown changes that are indicative of liver obstruction or sclerosing cholangitis, whilst biliary imaging demonstrated dilatation of intra- and extrahepatic bile ducts. However, discontinuation of ketamine is normally followed by slow improvement, with some research indicating the normalization of liver enzymes within 3 months of cessation [105]. The benefits of the restoration of nociceptive homeostasis may arguably outweigh the risk of hepatotoxicity [63], particularly as pain relief remains weeks after ketamine treatment is stopped. As such, it is imperative that regular liver function tests are performed for monitoring to prevent the development of hepatotoxicity.

Lastly, it is important that considerations into ketamine's safety and tolerability are explored in relation to dosage regimens as studies have shown pain relief is wholly dose-dependent. In NP, Ketamine is administered in sub-anesthetic doses. Whilst there is no clear consensus on optimal dose regimens, certain studies have attempted to optimize this to specific neuropathic sub-conditions. Increased infusion durations as well as the use of adjuvants to alleviate its psychomimetic side effects also factors in ketamine's efficacy [100,106]. More studies are needed to elucidate the long-term implications of its administration in subanesthetic doses.

On the whole, ketamine is generally well tolerated and safe in clinical settings. The most common side effects are minor, including but not limited to - nausea, vomiting and vertigo. The co-administration of adjuvants, such as benzodiazepines, counteracts and alleviates its side effect profile. The majority of studies conducted on NP found that most patients found the side effects acceptable due to its efficacy in providing pain relief [63,107]. Close monitoring of the CNS, cardiovascular and hepatic systems are essential to maintain safe clinical practice.

Pre-clinical Evidence


Whilst the precise mechanism by which ketamine elicits its analgesic effects against NP remains to be elucidated, it is thought to be via its inhibitory effects on the NMDAR, which is considered a well-known target for the treatment of NP [28,72,108-112]. Ketamine has been shown to inhibit NMDAR-mediated nociceptive transmission in the thalamus [113] and spinal cord [114], as well as attenuating the frequency-dependent increase in spinal cord neuron excitability induced by the stimulation of C-fiber primary afferent neurons [114,115]. Due to ketamine's ability to attenuate the onslaught of nociceptive input from the spinal cord to the brain, in addition to its enhancement of descending inhibition and anti-inflammatory effects [116,117], ketamine is considered a potential alternative to traditional treatments of chronic pain syndromes ketamine produces [63,72]. Animal studies have consistently demonstrated the critical role that NMDAR activation has in nerve injury models, as well as the modifications of these changes when pre-empted by NMDA antagonist administration [118,119]. However, it is important to note that a recent meta-analysis of therapeutic agents in the management of NP did not find significant evidence in favour of the use of ketamine or other NMDA antagonists [13].

In addition to its effects on the NMDAR, ketamine's analgesic effects are also dependent on various other receptor systems, including monoaminergic [120], opioidergic [121], muscarinic and dopaminergic pathways, as well as microglial calcium-activated K+ channels, toll-like receptor 3 [122], and other purinergic, cholinergic and adenosine systems [76,123]. Studies investigating the effects of ketamine in mice lacking the μ-opioid receptor have demonstrated that ketamine's analgesic effects are, at least in part, mediated via the opioidergic system [124].

Pre-clinical research investigating the role of ketamine in the management of NP is both limited and inconsistent. The clinical use of NMDAR inhibitors has classically been limited by a variety of side-effects related to the suppression of physiological functions mediated by the receptors. NP is etiologically heterogeneous and various maladaptive responses within the nociceptive pathway are responsible for its development, namely changes in gene expression, alterations in gene regulation within the central nervous system, adaptations to ion channel permeability resulting in ectopic activity, and central amplification secondary to synaptic facilitation of the neural axis. As a result of the varying aetiologies and mechanisms involved in the development of NP, its treatment has been classically considered, to varying degrees, ineffective, with NP syndromes characteristically displaying resistance to standard pharmacologic therapies, including tricyclic antidepressants, GABA-ergic agents, serotonin/norepinephrine reuptake inhibitors, and calcium channel agonists [125].

Pre-clinical studies investigating NP have demonstrated that local production of erythropoietin, mediated by the receptor-ß-common receptor complex [126], following peripheral nerve injury acts to limit neuronal damage and improve nerve function [127,128]. The expression of receptor-ß-common receptor complex, termed the innate repair receptor (IRR), has been shown to be induced following inflammation and tissue injury, resulting in the transduction of specific cellular responses involving endothelial nitric oxide synthase [129], for instance, and the subsequent local production of erythropoietin [130]. Animal models investigating the effects of erythropoietin on NP have found that administration of exogenous erythropoietin is associated with an attenuation in neuronal apoptosis and pro-inflammatory cytokine production, and a restoration in anti-inflammatory cytokine production, which phenotypically manifests as reduced allodynia and hyperalgesia [131]. The novel 11-amino acid peptide erythropoietin derivative, ARA290, has demonstrated similar analgesic effects against NP as ketamine, as well as similar effects on key markers of NP, including a reduction in the expression of mRNA of the NMDAR, astrocytes, microglia and chemokine ligand 2 [78]. An animal study conducted by Swartjes, et al. (2013) investigated whether ketamine and ARA290 shared a common pathway involving the IRR to induce analgesia [78]. The study found that ketamine produced profound antinociception, however,this occurred in conjunction with significant psychomotor side effects, and with both its analgesic and side effects occurring independently of an intact IRR. This study demonstrates that, whilst ketamine has the ability to induce significant antinociception, it concurrently results in unwanted side effects, with various clinical studies indicating that these can vary from psychotomimetic effects to arrhythmias, nausea and vomiting, hallucinations and visual impairment [54,63,105,132-138].

It is important to consider the use of ketamine in conjunction with other analgesics to elicit optimum analgesic effects. The most effective management of chronic pain is by a multimodal approach and, in the setting of mixed nociceptive/NP such as cancer pain, ketamine is often co-administered with opioid analgesics. Animal studies indicate that NMDAR inhibitors, such as ketamine, act to prevent the development of opioid-induced hyperalgesia [139-141]. The term opioid-induced hyperalgesia refers to the paradoxical state of nociceptive sensitization caused by the exposure to opioids, whereby an individual's pain perception may be heightened due to acute or chronic opioid treatment, resulting in difficult ongoing pain management. The ability of ketamine to potentially reduce the incidence of opioid side-effects indicates that the combination of ketamine and opioid may be effective in the management of mixed nociceptive/NP states, such as chronic cancer pain.

Clinical Evidence


Ketamine is mainly used as a dissociative anesthetic due its ability to preserve respiratory drive. However, there is mounting evidence in support of ketamine's use as an analgesic in NP ranging from small case studies to large randomized controlled clinical trials [77].

To date, four randomized controlled, double blind trials have examined the analgesic effect of long-term IV infusion of ketamine in NP. The most recent of which was conducted by Rigo, et al. who sought to establish the efficacy of both morphine and ketamine in NP [142]. Patients with NP refractory to conventional pain management models were split into three groups receiving; IV ketamine infusions only (n = 14), methadone only (n = 14) or methadone plus ketamine (n = 14). Pain scores were evaluated using a visual analogical scale (VAS) examining allodynia, burning and shooting pain. Whilst all treatment groups were found to be effective in reducing pain scores by at least 40%, the group receiving ketamine only achieved significantly higher improvements in pain relief. No differences were observed in reducing burning or shooting pain in any treatment groups, however, ketamine showed efficacy in reducing allodynia. This study concluded that subanesthetic ketamine is effective as a sole agent in NP management.

Amr examined the effect of ketamine on patients with a history of NP secondary to spinal cord injury, utilizing a multiple day subanesthetic infusion model [143]. Group 1 (n = 20) received an 80 mg IV infusion over five hours everyday for one week with 300 mg gabapentin, three times daily, as an adjunct. Group 2 (n = 20) were given a placebo instead of ketamine, with 300 mg gabapentin three times daily. The results showed that group 1 achieved significant reduction in pain scores during IV infusion and 2 weeks following initial treatment compared to group 2. There were no differences between the two groups thereafter. Ketamine was well tolerated and the side effects were both minimal and did not require medical intervention, where 3 out of 20 patients experienced short-lasting delusions.

Sigtermans, et al. evaluated whether S(+)-ketamine provides pain relief in CRPS-1 patients with severe chronic pain [63]. Subjects were evaluated pre-treatment, and a baseline of their pain scores were taken out of a scale of 1-10, with the mean being 7.2. Patients received either a 4.2-day IV infusion of subanesthetic ketamine (n = 30) or placebo (n = 30), where dosage was individualized to the efficacy of the analgesic effect and side effects experienced. Doses were increased in stepwise increments with a mean dose of 22.2 ± 2 mg/hr/kg. Significant pain reduction was observed in those receiving ketamine with a pain score of 2.68 ± 0.51 compared to placebo at 5.45 ± 0.48. Whilst patients on ketamine experienced nausea, vomiting and psychotropic effects, most found this acceptable. As such, one can deduce that the benefits arguably outweigh the risks.

This was followed up by Schwartzman, et al. who sought to establish the efficacy of ketamine in treating CRPS-1 with daily 4-hour IV ketamine infusions for 10 days, with a follow-up period of three months [105]. The patients were randomized into either a placebo (n = 10), where saline was substituted for ketamine, or treatment group (n = 9). All subjects received clonidine. The study showed that the treatment group demonstrated significant relief across all pain parameters that persisted 12 weeks post-treatment. The side effects experienced were mainly nausea, fatigue and headaches. Although this study was criticized by Bell and Moore [144] who argued the sample size limited the statistical significance of the results, it is clear that more studies are needed to further investigate ketamine's role in NP.

Niesters, et al. performed a meta-analysis on Schwartzman, Sigterman and Amr's randomized control trial at weeks 1 and 4 to elucidate Ketamine's efficacy in NP [70]. They found that its analgesic effect persists for at least 4 weeks, before rapidly declining suggesting that re-treatment is needed within 4-6 weeks of the initial administration. Therefore, they concluded re-admission poses financial implications.

Burst-Ketamine (BK) therapy has recently been advocated as an alternative pain management therapy. This is the infusion of subanesthetic ketamine with an opioid. Mak, et al. demonstrated a long-term anti-hyperalgesic effects persisting for 12 weeks when BK was administered, compared to 4 weeks with ketamine only [145]. An opioid-sparing effect was observed, translating into an improvement in anti-nociceptive response, which was only achieved with BK. This was the first pre-clinical study conducted on utilizing BK therapeutically in NP, and as such, further follow-up is necessary.

Topical use of ketamine has shown efficacy in achieving analgesia in various NP syndromes. This includes but is not limited to post-herpetic neuralgia, diabetic polyneuropathy and neuropathy secondary to spinal cord injuries. With NP growing in incidence in elderly patients, topical analgesia is garnering interest due to its minimal side effects and potential to be used as adjuncts to oral medication.

In a cohort size of 700 patients, Swaynok, et al. observed significant pain relief with side effects limited to application site reactions, in the administration of 4% Amitriptyline and 2% Ketamine (AmiKet) [146]. They argue that AmiKet has the potential in being first-line in treating post-herpetic neuralgia, as well as being an adjunct to oral medications to ensure both peripheral and central pain sites are targeted. Rabi, et al. conducted a smaller study on the application of topical ketamine 10% three times a day for two weeks in 5 patients with spinal cord injuries [147]. All patients reported pain relief ranging from 14-63%, with no adverse effects. Further studies with topical ketamine as an adjuvant has contributed to pain control [148]. On the whole, topical ketamine has shown efficacy in analgesia and further studies are needed.

Case studies have reported successful management of refractory NP with the use of ketamine [149,150]. Hanna, et al. managed a patient with Lichen Scleroses with a standard IV regimen, which reportedly abolished her pain syndrome completely [151]. The patient had been unresponsive to multiple pharmacological interventions, including opioids and anti-depressants. It was hypothesized that the immunomodulatory properties of ketamine was the underlying mechanism behind its therapeutic action.

In another case report, a patient with a history of Ehlers-danlos syndrome and spinal cord ischemic myelopathy presented with severe generalized body pain [152]. This was refractory to numerous pain therapies, and as such a 7-day ketamine infusion was administered reducing her pain score from 7-8 to 0-3. Secondary benefits included functional improvement in her mobility as well as a subsequent reduction in her dosage of pain medication, including opioids. Lo, et al. thus argue that ketamine could potentially reduce the chronic use of pain medication.

Conclusion


Neuropathic pain is a devastating and debilitating form of chronic pain that affects individual's physical and psychological well-being, quality of life and functionality. Recent pre-clinical evidence exists to suggest that ketamine elicits its analgesic effects in neuropathic pain states by inhibiting NMDA-mediated signaling pathways. Pre-clinical findings also indicate that ketamine may be a useful adjunct to traditional opioid analgesics to elicit optimum analgesic regimens. However, clinical evidence is currently limited, with only a small number of randomized control trials (n = 4) indicating the efficacy of ketamine in attenuating neuropathic pain, whilst no improvement was noted in the psychological state or functionality of patients suffering from chronic neuropathic pain. Furthermore, both pre-clinical and clinical data continue to suggest that ketamine administration is associated with a variety of unwanted side-effects affecting the cardiovascular, hepatic and nervous systems, manifesting as tachycardia, systemic and pulmonary hypertension, dizziness, hallucinations, psychosis, anxiety, paranoia and a schizoid-like state. Despite evidence for ketamine's analgesic effects in neuropathic pain states, due to its extensive side-effect profile, it is likely that ketamine should be restricted to patients with treatment-resistant, refractory neuropathic pain. Ketamine has always been classically considered as a drug that requires close monitoring due to its anesthetic and sedative effects. In order for ketamine to be a viable option in the management of neuropathic pain in the outpatient setting, tailored and smart dosing regimens are necessary and frequent input from clinicians is required in order to monitor patients and avoid toxicity or abuse. Whether outpatient or at-home, ketamine monitoring would be feasible in clinical practice remains to be elucidated. Further well-powered randomized control trials are certainly warranted in order to be confident of ketamine's analgesic efficacy and to further understand its side effect profile. This is pertinent in order for clinicians to make informed decisions regarding the risks and benefits associated with its use.

Acknowledgement


The work was partially supported by the BOC Chair grant, RCoA, London, UK.

References


  1. Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, et al. A new definition of neuropathic pain. Pain 2011;152(10):2204-5. PMID: 21764514.
  2. Baron R. Mechanisms of disease: neuropathic pain-a clinical perspective. Nat Clin Pract Neurol 2006;2(2):95-106. PMID: 16932531.
  3. Jensen MP, Chodroff MJ, Dworkin RH. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology 2007;68(15):1178-82. PMID: 17420400.
  4. van der Schans CP, Geertzen JH, Schoppen T, Dijkstra PU. Phantom pain and health-related quality of life in lower limb amputees. J Pain Symptom Manage 2002;24(4):429-36. PMID: 12505212.
  5. Atroshi I, Gummesson C, Johnsson R, Sprinchorn A. Symptoms, disability, and quality of life in patients with carpal tunnel syndrome. J Hand Surg Am 1999;24(2):398-404. PMID: 10194028.
  6. Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH, et al. Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: a review. Pain Med 2007;8 Suppl 2:S50-62. PMID: 17714116.
  7. Benbow SJ, Wallymahmed ME, MacFarlane IA. Diabetic peripheral neuropathy and quality of life. Qjm 1998;91(11):733-7. PMID: 10024935.
  8. Gustorff B, Dorner T, Likar R, Grisold W, Lawrence K, et al. Prevalence of self-reported neuropathic pain and impact on quality of life: a prospective representative survey. Acta Anaesthesiol Scand 2008;52(1):132-6. PMID: 17976220.
  9. Haythornthwaite JA, Benrud-Larson LM. Psychological aspects of neuropathic pain. Clin J Pain 2000;16(2 Suppl):S101-5. PMID: 10870748.
  10. Kemler MA, de Vet HC. Health-related quality of life in chronic refractory reflex sympathetic dystrophy (complex regional pain syndrome type I). J Pain Symptom Manage 2000;20(1):68-76. PMID: 10946171.
  11. Smith BH, Torrance N, Bennett MI, Lee AJ. Health and quality of life associated with chronic pain of predominantly neuropathic origin in the community. Clin J Pain 2007;23(2):143-9. PMID: 17237663.
  12. Davies L, Cossins L, Bowsher D, Drummond M. The cost of treatment for post-herpetic neuralgia in the UK. Pharmacoeconomics 1994;6(2):142-8. PMID: 10147439.
  13. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150(3):573-81. PMID: 20705215.
  14. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010;9(8):807-19. PMID: 20650402.
  15. Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A. Ketamine*. J Pain Symptom Manage 2011;41(3):640-9. PMID: 21419322.
  16. Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008;136(3):380-7. PMID: 17888574.
  17. May S, Serpell M. Diagnosis and assessment of neuropathic pain. F1000 Med Rep 2009;1:10.3410/M1-76. PMID: 20948703.
  18. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014;155(4):654-62. PMID: 24291734.
  19. Dieleman JP, Kerklaan J, Huygen FJ, Bouma PA, Sturkenboom MC. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 2008;137(3):681-8. PMID: 18439759.
  20. Jih JS, Chen YJ, Lin MW, Chen YC, Chen TJ, et al. Epidemiological features and costs of herpes zoster in Taiwan: a national study 2000 to 2006. Acta Derm Venereol 2009;89(6):612-6. PMID: 19997693.
  21. Hall GC, Carroll D, Parry D, McQuay HJ. Epidemiology and treatment of neuropathic pain: the UK primary care perspective. Pain 2006;122(1-2):156-62. PMID: 16545908.
  22. Hall GC, Carroll D, McQuay HJ. Primary care incidence and treatment of four neuropathic pain conditions: a descriptive study, 2002-2005. BMC Fam Pract 2008;9:26,2296-9-26. PMID: 18460194.
  23. Katusic S, Williams DB, Beard CM, Bergstralh E, Kurland LT. Incidence and clinical features of glossopharyngeal neuralgia, Rochester, Minnesota, 1945-1984. Neuroepidemiology 1991;10(5-6):266-75. PMID: 1798429.
  24. Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep 2012;16(3):191-8. PMID: 22395856.
  25. Ohayon MM, Stingl JC. Prevalence and comorbidity of chronic pain in the German general population. J Psychiatr Res 2012;46(4):444-50. PMID: 22265888.
  26. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006;7(4):281-9. PMID: 16618472.
  27. Toth C, Lander J, Wiebe S. The prevalence and impact of chronic pain with neuropathic pain symptoms in the general population. Pain Med 2009;10(5):918-29. PMID: 19594844.
  28. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32:1-32. PMID: 19400724.
  29. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50(3):355-63. PMID: 1333581.
  30. Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol 2008;64(6):644-53. PMID: 19107992.
  31. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52(1):77-92. PMID: 17015228.
  32. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Na v 1.7 and human pain disorders. Trends Neurosci 2007;30(11):555-63. PMID: 17950472.
  33. Ishikawa K, Tanaka M, Black JA, Waxman SG. Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy. Muscle Nerve 1999;22(4):502-7. PMID: 10204786.
  34. Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004;361(1-3):184-7. PMID: 15135924.
  35. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin 2007;45(2):27-37. PMID: 17426506.
  36. Sommer C, Schmidt C, George A. Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp Neurol 1998;151(1):138-42. PMID: 9582261.
  37. Sorkin LS, Doom CM. Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J Peripher Nerv Syst 2000;5(2):96-100. PMID: 10905468.
  38. Obreja O, Schmelz M, Poole S, Kress M. Interleukin-6 in combination with its soluble IL-6 receptor sensitises rat skin nociceptors to heat, in vivo. Pain 2002;96(1-2):57-62. PMID: 11932061.
  39. Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci 2000;20(16):6289-93. PMID: 10934280.
  40. Staaf S, Oerther S, Lucas G, Mattsson JP, Ernfors P. Differential regulation of TRP channels in a rat model of neuropathic pain. Pain 2009;144(1-2):187-99. PMID: 19446956.
  41. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A 1999;96(14):7723-30. PMID: 10393888.
  42. Stamboulian S, Choi JS, Ahn HS, Chang YW, Tyrrell L, et al. ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J Neurosci 2010;30(5):1637-47. PMID: 20130174.
  43. Hudmon A, Choi JS, Tyrrell L, Black JA, Rush AM, et al. Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. J Neurosci 2008;28(12):3190-201. PMID: 18354022.
  44. Abbadie C, Besson JM. C-fos expression in rat lumbar spinal cord following peripheral stimulation in adjuvant-induced arthritic and normal rats. Brain Res 1993;607(1-2):195-204. PMID: 8481796.
  45. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci 2004;24(20):4832-9. PMID: 15152043.
  46. Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, et al. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 2001;21(6):1868-75. PMID: 11245671.
  47. Baron R. Mechanisms of disease: neuropathic pain-a clinical perspective. Nat Clin Pract Neurol 2006;2(2):95-106. PMID: 16932531.
  48. Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 2001;8(1):1-10. PMID: 11162235.
  49. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, et al. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 2002;22(15):6724-31. PMID: 12151551.
  50. Zhao H, Alam A, Chen Q, A Eusman M, Pal A, et al. The role of microglia in the pathobiology of neuropathic pain development: what do we know?. Br J Anaesth 2017;118(4):504-16. PMID: 28403399.
  51. PubChem Compound Database; CID=3821. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/3821. Accessed 10/13, 2017.
  52. Anirudda Pai MH. Ketamine. Continuing Education in Anaesthesia Critical Care & Pain British Journal of Anaesthesia. 2nd ed.British Journal of Anaesthesia; 2007. p. 59-63.
  53. Domino EF. Taming the ketamine tiger. 1965. Anesthesiology 2010;113(3):678-84. PMID: 20693870.
  54. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003;97(6):1730-9. PMID: 14633551.
  55. Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?. J Clin Psychiatry 2017;78(7):e852-7. PMID: 28749092.
  56. Jones GM, Wiss AL, Goyal N, Chang JJ. Successful Use of Ketamine for Central Neurogenic Hyperventilation: A Case Report. Neurohospitalist 2017;7(4):192-5. PMID: 28974998.
  57. Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother 2002;16(3):27-35. PMID: 14640353.
  58. Jonkman K, Duma A, Velzen M, Dahan A. Ketamine inhalation. Br J Anaesth 2017;118(2):268-9. PMID: 28100533.
  59. Jonkman K, Duma A, Olofsen E, Henthorn T, van Velzen M, et al. Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers. Anesthesiology 2017;127(4):675-83. PMID: 28759464.
  60. Wieber J, Gugler R, Hengstmann JH, Dengler HJ. Pharmacokinetics of ketamine in man. Anaesthesist 1975;24(6):260-3. PMID: 1155748.
  61. Grant IS, Nimmo WS, Clements JA. Lack of effect of ketamine analgesia on gastric emptying in man. Br J Anaesth 1981;53(12):1321-3. PMID: 7317250.
  62. Dahan A, Olofsen E, Sigtermans M, Noppers I, Niesters M, et al. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. Eur J Pain 2011;15(3):258-67. PMID: 20638877.
  63. Sigtermans MJ, van Hilten JJ, Bauer MC, Arbous MS, Marinus J, et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain 2009;145(3):304-11. PMID: 19604642.
  64. Christoph T, Schiene K, Englberger W, Parsons CG, Chizh BA. The antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism. Neuropharmacology 2006;51(1):12-7. PMID: 16616769.
  65. Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 2002;30(7):853-8. PMID: 12065445.
  66. Sigtermans M, Dahan A, Mooren R, Bauer M, Kest B, et al. S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. Anesthesiology 2009;111(4):892-903. PMID: 19741495.
  67. Olofsen E, Noppers I, Niesters M, Kharasch E, Aarts L, et al. Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers. Anesthesiology 2012;117(2):353-64. PMID: 22692377.
  68. Goldberg ME, Torjman MC, Schwartzman RJ, Mager DE, Wainer IW. Pharmacodynamic profiles of ketamine (R)- and (S)- with 5-day inpatient infusion for the treatment of complex regional pain syndrome. Pain Physician 2010;13(4):379-87. PMID: 20648207.
  69. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet 2016;55(9):1059-77. PMID: 27028535.
  70. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol 2014;77(2):357-67. PMID: 23432384.
  71. Okutsu Y, Takahashi Y, Nagase M, Shinohara K, Ikeda R, et al. Potentiation of NMDA receptor-mediated synaptic transmission at the parabrachial-central amygdala synapses by CGRP in mice. Mol Pain 2017;13:1744806917709201. PMID: 28604219.
  72. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003;97(4):1108-16. PMID: 14500166.
  73. Aiyer R, Mehta N, Gungor S, Gulati A. A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice. Clin J Pain 2017;. PMID: 28877137.
  74. Kaka U, Saifullah B, Abubakar AA, Goh YM, Fakurazi S, et al. Serum concentration of ketamine and antinociceptive effects of ketamine and ketamine-lidocaine infusions in conscious dogs. BMC Vet Res 2016;12(1):198,016-0815-4. PMID: 27612660.
  75. Hillhouse TM, Negus SS. Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats. Eur J Pain 2016;20(8):1229-40. PMID: 26914635.
  76. Chizh BA. Low dose ketamine: a therapeutic and research tool to explore N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways. J Psychopharmacol 2007;21(3):259-71. PMID: 17591654.
  77. Niesters M, Dahan A. Pharmacokinetic and pharmacodynamic considerations for NMDA receptor antagonists in the treatment of chronic neuropathic pain. Expert Opin Drug Metab Toxicol 2012;8(11):1409-17. PMID: 22871026.
  78. Swartjes M, Niesters M, Heij L, Dunne A, Aarts L, et al. Ketamine does not produce relief of neuropathic pain in mice lacking the beta-common receptor (CD131). PLoS One 2013;8(8):e71326. PMID: 23936499.
  79. Ghelardini C, Galeotti N, Vivoli E, Norcini M, Zhu W, et al. Molecular interaction in the mouse PAG between NMDA and opioid receptors in morphine-induced acute thermal nociception. J Neurochem 2008;105(1):91-100. PMID: 17996026.
  80. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002;22(18):8312-23. PMID: 12223586.
  81. Weinbroum AA. Postoperative hyperalgesia-A clinically applicable narrative review. Pharmacol Res 2017;120:188-205. PMID: 28365208.
  82. Zhang Y, Ahmed S, Vo T, St Hilaire K, Houghton M, et al. Increased pain sensitivity in chronic pain subjects on opioid therapy: a cross-sectional study using quantitative sensory testing. Pain Med 2015;16(5):911-22. PMID: 25376890.
  83. Chen L, Sein M, Vo T, Amhmed S, Zhang Y, et al. Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia. J Opioid Manag 2014;10(6):383-93. PMID: 25531956.
  84. Amin P, Roeland E, Atayee R. Case report: efficacy and tolerability of ketamine in opioid-refractory cancer pain. J Pain Palliat Care Pharmacother 2014;28(3):233-42. PMID: 25102039.
  85. Jendoubi A, Naceur IB, Bouzouita A, Trifa M, Ghedira S, et al. A comparison between intravenous lidocaine and ketamine on acute and chronic pain after open nephrectomy: A prospective, double-blind, randomized, placebo-controlled study. Saudi J Anaesth 2017;11(2):177-84. PMID: 28442956.
  86. Nobrega R, Sheehy KA, Lippold C, Rice AL, Finkel JC, et al. Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease. Pediatr Res 2017;. PMID: 28902183.
  87. Maher DP, Zhang Y, Ahmed S, Doshi T, Malarick C, et al. Chronic Opioid Therapy Modifies QST Changes After Ketamine Infusion in Chronic Pain Patients. J Pain 2017;. PMID: 28802882.
  88. Bowers KJ, McAllister KB, Ray M, Heitz C. Ketamine as an Adjunct to Opioids for Acute Pain in the Emergency Department: A Randomized Controlled Trial. Acad Emerg Med 2017;24(6):676-85. PMID: 28177167.
  89. Marchetti F, Coutaux A, Bellanger A, Magneux C, Bourgeois P, et al. Efficacy and safety of oral ketamine for the relief of intractable chronic pain: A retrospective 5-year study of 51 patients. Eur J Pain 2015;19(7):984-93. PMID: 25381898.
  90. Caffino L, Piva A, Mottarlini F, Di Chio M, Giannotti G, et al. Ketamine Self-Administration Elevates alphaCaMKII Autophosphorylation in Mood and Reward-Related Brain Regions in Rats. Mol Neurobiol 2017;. PMID: 28948570.
  91. Liu Q, Xu TY, Zhang ZB, Leung CK, You DY, et al. Effects of co-administration of ketamine and ethanol on the dopamine system via the cortex-striatum circuitry. Life Sci 2017;179:1-8. PMID: 28454718.
  92. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 2001;25(4):455-67. PMID: 11557159.
  93. Yasuda K, Hayashi Y, Yoshida T, Kashiwagi M, Nakagawa N, et al. Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults. Transl Psychiatry 2017;7(2):e1047. PMID: 28244984.
  94. Ham S, Kim TK, Chung S, Im HI. Drug Abuse and Psychosis: New Insights into Drug-induced Psychosis. Exp Neurobiol 2017;26(1):11-24. PMID: 28243163.
  95. Wolff K, Winstock AR. Ketamine : from medicine to misuse. CNS Drugs 2006;20(3):199-218. PMID: 16529526.
  96. Chatterjee M, Ganguly S, Srivastava M, Palit G. Effect of 'chronic' versus 'acute' ketamine administration and its 'withdrawal' effect on behavioural alterations in mice: implications for experimental psychosis. Behav Brain Res 2011;216(1):247-54. PMID: 20699106.
  97. Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology (Berl) 2006;188(4):408-24. PMID: 17006715.
  98. Ding R, Li Y, Du A, Yu H, He B, et al. Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: another understanding of ketamine CNS toxicity. Sci Rep 2016;6:38771. PMID: 27934938.
  99. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction 2010;105(1):121-33. PMID: 19919593.
  100. Wang X, Ding X, Tong Y, Zong J, Zhao X, et al. Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials. J Anesth 2014;28(6):821-7. PMID: 24859931.
  101. Timm C, Linstedt U, Weiss T, Zenz M, Maier C. Sympathomimetic effects of low-dose S(+)-ketamine. Effect of propofol dosage. Anaesthesist 2008;57(4):338-46. PMID: 18270675.
  102. Noppers IM, Niesters M, Aarts LP, Bauer MC, Drewes AM, et al. Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain 2011;152(9):2173-8. PMID: 21546160.
  103. Bell RF. Ketamine for chronic noncancer pain: concerns regarding toxicity. Curr Opin Support Palliat Care 2012;6(2):183-7. PMID: 22436323.
  104. Kalkan Y, Tomak Y, Altuner D, Tumkaya L, Bostan H, et al. Hepatic effects of ketamine administration for 2 weeks in rats. Hum Exp Toxicol 2014;33(1):32-40. PMID: 23386779.
  105. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain 2009;147(1-3):107-15. PMID: 19783371.
  106. Maher DP, Chen L, Mao J. Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization. Anesth Analg 2017;124(2):661-74. PMID: 28067704.
  107. Cvrcek P. Side effects of ketamine in the long-term treatment of neuropathic pain. Pain Med 2008;9(2):253-7. PMID: 18298710.
  108. Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci 2005;6(7):521-32. PMID: 15995723.
  109. Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med 2005;257(2):139-55. PMID: 15656873.
  110. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest 2010;120(11):3779-87. PMID: 21041960.
  111. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152(3 Suppl):S2-15. PMID: 20961685.
  112. Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000;20(5):358-73. PMID: 11068158.
  113. Salt TE, Wilson DG, Prasad SK. Antagonism of N-methylaspartate and synaptic responses of neurones in the rat ventrobasal thalamus by ketamine and MK-801. Br J Pharmacol 1988;94(2):443-8. PMID: 3293684.
  114. Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in 'wind-up' of class 2 neurones in the dorsal horn of the rat. Brain Res 1987;424(2):402-6. PMID: 2823998.
  115. Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol 2011;4(3):379-88. PMID: 21686074.
  116. Niesters M, Khalili-Mahani N, Martini C, Aarts L, van Gerven J, et al. Effect of subanesthetic ketamine on intrinsic functional brain connectivity: a placebo-controlled functional magnetic resonance imaging study in healthy male volunteers. Anesthesiology 2012;117(4):868-77. PMID: 22890117.
  117. Hirota K, Lambert DG. Ketamine: new uses for an old drug?. Br J Anaesth 2011;107(2):123-6. PMID: 21757548.
  118. Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, et al. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 1996;67(1):69-77. PMID: 8895233.
  119. Wilson JA, Nimmo AF, Fleetwood-Walker SM, Colvin LA. A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation. Pain 2008;135(1-2):108-18. PMID: 17583431.
  120. Lindefors N, Barati S, O'Connor WT. Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex. Brain Res 1997;759(2):205-12. PMID: 9221938.
  121. Eide PK, Stubhaug A, Breivik H, Oye I. Reply to S.T. Meller: Ketamine: relief from chronic pain through actions at the NMDA receptor. Pain 1997;72(1-2):289-91. PMID: 9272819.
  122. Mei XP, Zhou Y, Wang W, Tang J, Wang W, et al. Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain. Neurosignals 2011;19(1):44-53. PMID: 21389680.
  123. Persson J. Wherefore ketamine?. Curr Opin Anaesthesiol 2010;23(4):455-60. PMID: 20531172.
  124. Sarton E, Teppema LJ, Olievier C, Nieuwenhuijs D, Matthes HW, et al. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Anesth Analg 2001;93(6):1495,500, table of contents. PMID: 11726430.
  125. Fallon MT. Neuropathic pain in cancer. Br J Anaesth 2013;111(1):105-11. PMID: 23794652.
  126. Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 2004;101(41):14907-12. PMID: 15456912.
  127. Lipton SA. Erythropoietin for neurologic protection and diabetic neuropathy. N Engl J Med 2004;350(24):2516-7. PMID: 15190146.
  128. Sekiguchi Y, Kikuchi S, Myers RR, Campana WM. ISSLS prize winner: Erythropoietin inhibits spinal neuronal apoptosis and pain following nerve root crush. Spine (Phila Pa 1976) 2003;28(23):2577-84. PMID: 14652474.
  129. Broughton SE, Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA, et al. The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol Rev 2012;250(1):277-302. PMID: 23046136.
  130. Brines M, Cerami A. The receptor that tames the innate immune response. Mol Med 2012;18:486-96. PMID: 22183892.
  131. Swartjes M, van Velzen M, Niesters M, Aarts L, Brines M, et al. ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain 2014;10:13,8069-10-13. PMID: 24529189.
  132. Kim K, Mishina M, Kokubo R, Nakajima T, Morimoto D, et al. Ketamine for acute neuropathic pain in patients with spinal cord injury. J Clin Neurosci 2013;20(6):804-7. PMID: 23618680.
  133. Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol 2008;(182):313-33. doi(182):313-33. PMID: 18175098.
  134. Eide PK, Jorum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994;58(3):347-54. PMID: 7838584.
  135. Rabben T, Skjelbred P, Oye I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain. J Pharmacol Exp Ther 1999;289(2):1060-6. PMID: 10215688.
  136. Rabben T, Oye I. Interindividual differences in the analgesic response to ketamine in chronic orofacial pain. Eur J Pain 2001;5(3):233-40. PMID: 11558979.
  137. Eichenberger U, Neff F, Sveticic G, Bjorgo S, Petersen-Felix S, et al. Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg 2008;106(4):1265,73, table of contents. PMID: 18349204.
  138. Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol 2012;30(29):3611-7. PMID: 22965960.
  139. Juni A, Klein G, Kest B. Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: evidence for multiple diverse hyperalgesic systems. Brain Res 2006;1070(1):35-44. PMID: 16409995.
  140. Juni A, Klein G, Pintar JE, Kest B. Nociception increases during opioid infusion in opioid receptor triple knock-out mice. Neuroscience 2007;147(2):439-44. PMID: 17544222.
  141. van Dorp EL, Kest B, Kowalczyk WJ, Morariu AM, Waxman AR, et al. Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology 2009;110(6):1356-63. PMID: 19461298.
  142. Rigo FK, Trevisan G, Godoy MC, Rossato MF, Dalmolin GD, et al. Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Physician 2017;20(3):207-15. PMID: 28339433.
  143. Amr YM. Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double blind trial. Pain Physician 2010;13(3):245-9. PMID: 20495588.
  144. Bell RF, Moore RA. Intravenous ketamine for CRPS: Making too much of too little?. Pain 2010;150(1):10-1. PMID: 20347222.
  145. Mak P, Broadbear JH, Kolosov A, Goodchild CS. Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats. Pain Med 2015;16(9):1781-93. PMID: 25800174.
  146. Sawynok J, Zinger C. Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain. Expert Opin Pharmacother 2016;17(4):601-9. PMID: 26809783.
  147. Rabi J, Minori J, Abad H, Lee R, Gittler M. Topical Ketamine 10% for Neuropathic Pain in Spinal Cord Injury Patients: An Open-Label Trial. Int J Pharm Compd 2016;20(6):517-20. PMID: 28339391.
  148. Weinbroum AA, Zur E. Patient-tailored combinations of systemic and topical preparations for localized peripheral neuropathic pain: a two-case report. J Pain Palliat Care Pharmacother 2015;29(1):27-33. PMID: 25594152.
  149. Hanna AF, Abraham B, Hanna A, Smith AJ. Effects of intravenous ketamine in a patient with post-treatment Lyme disease syndrome. Int Med Case Rep J 2017;10:305-8. PMID: 28860873.
  150. Liman S, Cheung CW, Wong KL, Tai W, Qiu Q, et al. Preventive Treatment with Ketamine Attenuates the Ischaemia-Reperfusion Response in a Chronic Postischaemia Pain Model. Oxid Med Cell Longev 2015;2015:380403. PMID: 26161236.
  151. Hanna AF, Armstrong JS, Smith AJ. Effects of Intravenous Ketamine Infusions in a Neuropathic Pain Patient with Lichen Sclerosus et Atrophicus. Case Rep Dermatol 2016;8(2):164-70. PMID: 27462225.
  152. Lo TC, Yeung ST, Lee S, Skavinski K, Liao S. Reduction of central neuropathic pain with ketamine infusion in a patient with Ehlers-Danlos syndrome: a case report. J Pain Res 2016;9:683-7. PMID: 27695362.