Ketamine for pain management
Key Points There is good evidence that perioperative ketamine decreases postoperative pain scores and opioid requirements, but there is a lack of consensus on dose, for both bolus and infusion. Despite limited evidence, a trial of low-dose intravenous or subcutaneous ketamine adjuvant to morphine may be warranted in refractory cancer pain. There is only very limited evidence for the use of ketamine in chronic noncancer pain and concerns and a lack of safety data concerning long-term or repeated treatment. Importantly, there is no strong evidence to support the current practice of treating chronic noncancer pain with repeated intravenous infusions. Ketamine has dose-dependent adverse effects, and there are good arguments for avoiding high doses. Spinal administration is associated with neurotoxicity, whereas oral ketamine has low bioavailability and is associated with adverse effects. 1. Background 1.1. Basic pharmacology and mechanisms of action of ketamine Ketamine is commonly used as an analgesic in emergency medicine and as an adjuvant drug in the perioperative setting. In addition, it is used as a third-line adjuvant drug for opioid-resistant pain in palliative care and for intractable chronic noncancer pain. More recently, ketamine is increasingly being used to treat major depression and other mood disorders. Ketamine is a phencyclidine derivative that was developed in the 1960s as an anaesthetic agent. The most important pharmacological properties of ketamine are due to it being a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, and its analgesic action at subanaesthetic dose is believed to be primarily due to NMDA receptor antagonism in the brain and spinal cord.33 The NMDA receptor is important for learning, memory, and synaptic plasticity. Regarding pain, the NMDA receptor is involved in the amplification of pain signals, the development of central sensitization, and opioid tolerance.49 Ketamine has been shown to have antihyperalgesic effects and to reduce or reverse opioid tolerance.22,24 Ketamine also interacts with other receptors and channels, including nicotinic and muscarinic acetylcholine receptors, opioid receptors, monoaminergic receptors, and voltage-sensitive sodium channels.41 It enhances endogenous antinociceptive systems, increasing the descending inhibitory serotoninergic pathway.33 Recent research indicates that ketamine may also modulate (suppress) pain transmission by limiting astrocyte and microglial activation.46 Ketamine gives robust and rapid relief of major depression and suicidal ideation.1 The mechanism for this effect is as yet not fully elucidated, but major depressive disorder is associated with synaptic downregulation in the prefrontal cortex and hippocampus, and it is believed that ketamine causes a glutamate surge that leads to a series of events resulting in synaptogenesis and reversal of the negative effects of depression and chronic stress.1 A recent functional magnetic resonance imaging study in patients with treatment-resistant depression compared with healthy volunteers demonstrated that ketamine normalized depression-related prefrontal dysconnectivity.2 Ketamine has anti-inflammatory effects, modulating the production of different proinflammatory mediators. A recent study using a rabbit model of gonarthrosis found that ketamine suppressed the inflammatory response in osteoarthritis,28 whereas a systematic review concluded that intraoperative ketamine reduces the postoperative IL-6 inflammatory response in surgical patients.15 The most commonly reported adverse effects of ketamine are psychotomimetic (hallucinations, agitation, anxiety, dysphoria, and euphoria). Administration of ketamine may also cause dizziness, nausea, sedation, and tachycardia. Ketamine's adverse effects are dose-dependent. At low dose, it acts as an NMDA receptor antagonist, providing an analgesic effect; but at higher doses, it acts on other receptors and channels including dopamine D2 receptors, monoaminergic receptors, and opioid receptors.62 Ketamine dose dependently inhibits monoamine transporters, and it has been suggested that this may be one mechanism behind its psychotomimetic adverse effects.41 Chronic abuse of ketamine is associated with a range of adverse effects, some of which have also been reported in pain patients treated with ketamine (Tables 1 and 2).Table 1: Adverse effects of ketamine, other than psychotomimetic, reported in cancer/palliative care pain management.Table 2: Adverse effects of ketamine, other than psychotomimetic, reported in chronic noncancer pain management.1.2. Pharmacokinetics and administration of ketamine Ketamine is available as a racemic mixture or as the S(+) enantiomer that is approximately twice as potent as racemic ketamine and about 4 times as potent as the R(−) enantiomer.33 Ketamine is N-demethylated by liver microsomes into the major metabolite of racemic ketamine, norketamine, which is rapidly metabolized to ketamine's major secondary metabolite, 6-hydroxynorketamine, and to the lesser metabolites 4-hydroxyketamine and 6-hydroxyketamine.33 Ketamine has been shown to have antinociceptive effects and to reduce opioid tolerance, whereas norketamine has been shown to have antinociceptive properties in animal studies, but little is known about its analgesic effects in humans. A study in healthy volunteers found that S(+)-norketamine after S(+) ketamine dosing did not have significant antinociceptive properties and even made a negative contribution to S(+) ketamine analgesia.39 Six-hydroxynorketamine in an animal model failed both to demonstrate antinociceptive properties and to attenuate opioid tolerance.26 Ketamine may be given by multiple routes of administration including intravenous (IV), subcutaneous, oral, intranasal, transdermal, and spinal (epidural and intrathecal). Spinal administration of ketamine has been shown to be associated with neurotoxicity, safety data are lacking and no NMDA receptor antagonists have been approved for neuraxial use in humans.57 The oral bioavailability of ketamine is low, reportedly 17% to 24% for oral racemic ketamine and 8% to 11% for oral S(+)-ketamine.41 After oral intake of ketamine, norketamine plasma concentrations are much higher than those of the parent drug.41 Ketamine does not cause respiratory depression and does not decrease blood pressure, making it a useful drug in emergency medicine and intensive care, although there are certain concerns because of its effect on intracranial pressure and ocular pressure. The use of ketamine in emergency medicine and intensive care is beyond the scope of this review. Ketamine's antihyperalgesic, antidepressant, and anti-inflammatory effects, together with its beneficial interactions with opioids, including reduction of opioid tolerance, make it an especially interesting drug to use in pain management. However, depending on the clinical setting, the extent to which ketamine is clinically useful depends not only on its efficacy and tolerability but also on other factors such as ease of administration, costs, and long-term safety. The best evidence for efficacy and tolerability comes from systematic reviews of randomized controlled trials (RCTs), whereas case reports provide valuable information on adverse effects. In this review, we will examine the current evidence for the benefits and harms of ketamine and its clinical usefulness in pain management. 2. Ketamine for acute postoperative pain There is a large body of literature addressing the use of ketamine in the perioperative setting. Adjuvant treatment with IV racemic, or S(+) ketamine is common, to improve postoperative pain relief and reduce opioid requirements. Epidural ketamine has also been used in this setting. In some cases, ketamine has been used with the aim of preventing chronic postoperative pain. 2.1. Evidence for efficacy and adverse effects A search of PubMed on February 23, 2018, using the terms “ketamine” AND “postoperative pain” and the filter “systematic reviews” yielded 56 hits, 11 of which were systematic reviews addressing perioperative ketamine for acute or chronic postoperative pain4,8,16,21,30,36,42,55,59,60,63 (Table 3). A recently completed Cochrane review,14 currently under review, has also been included.Table 3: Systematic reviews of ketamine for postoperative pain.Perioperative ketamine decreased postoperative pain scores,4,8,16,21,30,36,42,55,60,63 increased the time to first analgesic request,21,60 and reduced postoperative opioid requirements.4,8,16,21,42,55,59,60,63 Ketamine also reduced postoperative nausea and/or vomiting.4,21,36,55,60,63 Interestingly, Laskowski et al.21 found that ketamine had significant analgesic benefit for major procedures involving the upper abdomen and thorax, associated with high pain scores or high opioid requirements. This finding was also reported by the most recent Cochrane review.14 One review that focused on ketamine for persistent postsurgical pain30 did not find an overall reduced risk of developing chronic postoperative pain in the ketamine group compared with placebo. However, when exclusively IV ketamine studies were analysed, they demonstrated statistically significant risk reduction at 3 and 6 months. According to the authors, this could have been due to spinal NMDA receptors playing only a minor role as targets for ketamine in postoperative pain, or due to ketamine having lower systemic efficacy when it is administered by the epidural route. Most systematic reviews report that perioperative ketamine was well tolerated, with adverse effects being mild or absent. Most studies provided dichotomous data on central nervous system adverse events.14 2.1.1. Clinical considerations Although most trials investigated ketamine given by the IV route, clinical regimens differed, especially regarding dose. Data from the review by Brinck et al.14 indicate that 77 of the 130 trials used racemic ketamine as an IV bolus, with 35 of these studies using a dose less than 0.25 mg/kg. Twenty-one studies used a bolus dose of 0.5 to 1 mg/kg. Forty-two trials used racemic ketamine as a continuous IV infusion, with the most common dose being 2 to 5 μg/kg/min. Ten trials used S(+) ketamine, of these 8 used a preincisional IV bolus (0.075–0.5 mg/kg), followed by an IV infusion (0.25–6.7 μg/kg/min). One trial used R(−) ketamine as an IV bolus (1 mg/kg). Ketamine seems most beneficial when pain scores are high, suggesting that it is primarily useful for surgery associated with high levels of postoperative pain. Given that ketamine reduces opioid requirements, it may also be indicated for subgroups such as opioid tolerant or opioid-dependent patients. 3. Ketamine for opioid-resistant pain in palliative care Ketamine is widely used as a third-line drug for cancer pain, when the pain has not responded to opioid in combination with drugs such as nonsteroidal anti-inflammatory drugs, amitriptyline, and gabapentinoids. Published case reports demonstrate that ketamine is used for refractory pain in palliative care in many countries, and that treatment regimens differ widely using IV, subcutaneous, oral, intrathecal, and topical routes of administration. A Cochrane review on ketamine as an adjuvant to opioid for cancer pain,9 first published in 2003, described 32 case reports involving 246 patients treated with ketamine. Doses ranged from 1 mg/kg/d as a subcutaneous infusion, to 600 mg/d as an IV infusion and 67.2 mg/d intrathecally. 3.1. Evidence for efficacy and adverse effects A simple search of PubMed using the terms “ketamine” AND “cancer” and the filter “systematic reviews” yielded 14 hits, 4 of which were systematic reviews on ketamine for cancer pain. Three of the 4 titles were different versions of the Cochrane review on ketamine as an adjuvant to opioid in cancer pain in adults, which has been twice updated, most recently in 2017.9 The fourth title was a comprehensive review of all available English language literature on ketamine for cancer pain in children and adults13 (Table 4).Table 4: Systematic reviews on ketamine for refractory cancer pain.The recently updated Cochrane review included 3 RCTs. Two small cross-over trials investigated IV ketamine in 2 doses31 or intrathecal ketamine58 as an adjuvant to morphine. Both trials found that ketamine reduced pain intensity and morphine requirements. A third larger trial with a parallel-group design and 185 participants investigated rapid titration of subcutaneous ketamine to high dose (500 mg) in participants who were using different opioids.18 In this trial, there was no difference between groups regarding patient-reported pain intensity, and there was almost twice the incidence of adverse effects in the ketamine group. Two serious adverse events (bradyarrhythmia and cardiac arrest) believed to be related to ketamine were reported in this trial. The update concluded that current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for refractory cancer pain, and that rapid dose escalation of ketamine to high dose (500 mg) does not seem to have clinical benefit and may be associated with serious adverse events. The review by Bredlau et al.,13 which used a comprehensive approach and less stringent methodology than the Cochrane review included 5 RCTs and 6 prospective uncontrolled trials on ketamine for cancer pain in adults. No RCTs in children were identified, but the authors considered 5 retrospective studies. The review found that ketamine reduced opioid requirements, and may improve pain control, at the same time noting the significant limitations of the current evidence and the wide variation in dosages, routes, duration, and frequency of ketamine administration in the published literature. The authors also expressed concerns regarding ketamine's neurotoxic effects, recommending that intrathecal administration and epidural administration should be avoided. The review concludes that “In children and adults with cancer pain that has not responded adequately to standard therapy, the literature supports considering ketamine as an adjuvant therapy.” Several reports have described neurotoxicity when ketamine was administered intrathecally in the palliative care setting.20,48,54 Abrupt cessation of a continuous subcutaneous infusion was reported to result in generalized hyperalgesia.34 Storr et al. reported 3 patients treated by a palliative care team who developed urological symptoms (frequency, haematuria, dysuria, and bladder pain) after oral ketamine.47 For reports of adverse effects of ketamine, other than psychotomimetic, in the management of refractory cancer pain, see Table 1. 3.1.1. Clinical considerations We concur with the review by Bredlau et al.13 that although the evidence is limited, ketamine may be useful as a third-line drug for selected patients with refractory cancer pain. Many of the case studies describe a dramatic effect of ketamine, but as yet, we are unable to identify characteristics of responders. The choice of opioid may be of importance because recent animal studies have shown that ketamine and norketamine attenuate morphine tolerance more effectively than oxycodone tolerance.25 There seem to be good arguments for keeping the ketamine dose low. Ketamine has dose-dependent adverse effects. Terminally ill cancer patients may have reduced hepatic function because of metastases and diminished liver perfusion. Hepatic impairment can cause reduced drug metabolism and significantly impaired clearance.37 Increased age has also been shown to be associated with substantially reduced ketamine clearance.23 Examples of low-dose regimens adjuvant to opioid, primarily morphine, are racemic ketamine 1 mg/kg/24 hours per day,7 or S(+) ketamine (0.5–2 mg/kg/24 hours) as an IV infusion, with careful individual titration.10 The evidence for efficacy and tolerability for ketamine in this setting is limited. It is undeniably challenging to conduct RCTs in this patient group. What then in theory could be the indications for ketamine treatment? When cancer pain or pain in a palliative care patient is refractory to opioid and adjuvant drugs, then ketamine may be an option. There are many reasons for pain in this patient group. Ketamine could be especially relevant when there are problems of opioid tolerance, a significant neuropathic pain component, inflammatory pain, depression, or any combination of these factors. In fact, this may be the pain patient group that is most likely to need a trial of ketamine and where the risk benefit ratio is the most beneficial. A trial of ketamine does not need to be lengthy and if there is no clear benefit, then ketamine treatment should be terminated. 4. Ketamine for chronic noncancer pain It is more difficult to formulate clear indications for the use of ketamine in chronic noncancer pain. Given ketamine's range of adverse effects and the lack of safety data concerning long-term treatment, there is good reason to be cautious when treating complex chronic pain problems with this drug. Possible indications could be refractory neuropathic or inflammatory pain with, or without, depression in carefully selected patients. Ketamine is increasingly being used as a third-line drug for refractory chronic noncancer pain. In this setting, it is commonly administered as intermittent IV infusions. Patients may be offered hospital admission and infusion treatment over several days. However, outpatient treatment seems to be on the increase, and in the United States, a large number of “ketamine clinics” have been established offering infusions for a variety of conditions, including chronic pain, depression, and other mood disorders. A Medscape report suggests that there may be more than 1000 such clinics currently operating in the United States.51 For chronic pain, these clinics offer a series of infusions on an outpatient basis, followed by “maintenance therapy” for example, involving monthly ketamine infusions.5 Although racemic ketamine is an inexpensive drug, patient costs associated with this treatment are high (supplemental digital content 1, https://links.lww.com/PR9/A25).5 4.1. Evidence for efficacy and adverse effects A search of PubMed on February 23, 2018, using the terms “ketamine” AND “chronic pain” and the filter “systematic reviews” yielded 20 hits, of which 4 were systematic reviews on ketamine for chronic noncancer pain in adults6,19,32,61 (Table 5).Table 5: Systematic reviews of ketamine for chronic noncancer pain.Of the 2 reviews published in 2018, Michelet et al.32 included only trials on ketamine for chronic pain in adults (Table The authors found evidence that ketamine was regarding the of the review, to decrease pain intensity at 4 after the of treatment. When only trials not to have a high risk of were they found evidence that ketamine was at 4 after treatment, suggesting a However, the clinical of this finding are because trial found the to be and in several of the included trials have been The authors the trials by et and to be at high risk of whereas the methodology and of the trial by et which was even of the number of patients had been have also been The carefully trial by et found that ketamine infusions pain relief for patients with complex pain but did not result in functional the authors in this trial was by adverse effects. times in these chronic pain RCTs were 1 11 and 3 trials on ketamine for chronic pain in adults et was associated with more adverse effects than placebo. The studies were regarding dose, of administration, and of treatment, and the authors of the review were unable to any treatment noting the need for et ketamine infusions for and and data from participants in However, only one of the included studies was an and retrospective studies were also of the studies used S(+) ketamine whereas one used racemic ketamine. The authors concluded that that ketamine may provide pain but that studies are to this Clinical considerations et when the lack of functional in the ketamine group more treatment, in combination with or could be ketamine treatment with is an important which as yet, has not been by any The literature reports on the and adverse effects of ketamine. There are also case reports concerning adverse effects in patients with chronic pain (Table et described in a patient treated for with oral ketamine. A patient with chronic pain developed uncontrolled pressure 1 after treatment with oral et described 3 of 6 patients treated with ketamine who developed after infusions. A patient with chronic pain after cancer and with no who treatment with ketamine developed 6 after et have recently reported upper such as pain and in of of ketamine treatment for and that patients with upper symptoms should be about the use of ketamine. It is not common that repeated administration of ketamine may cause such symptoms could in to repeated infusions of ketamine is but there is a that could be in the clinical setting. Ketamine's for should also be considered when patients are treated with intermittent IV infusions. Ketamine is a drug. In animal repeated administration in subanaesthetic causes a of drugs such as found the of studies to be concerning as to regarding the repeated use of ketamine, both and in the clinical report a patient treated for pain and depression who and developed an to ketamine (supplemental digital content ketamine's adverse effects are high should be avoided. a low dose of ketamine to an opioid, especially morphine, seems to improve pain However, combination treatment with drugs such as ketamine and opioid in a patient group with and where treatment may be or repeated multiple times may cause problems in Ketamine is a drug with complex mechanisms of action and many properties which make it interesting for pain management. However, treatment regimens differ widely and there are concerns regarding adverse effects. of ketamine are reported to cause a range of adverse effects and should be avoided. Ketamine has low oral and oral administration seems to be associated with a high of adverse effects. Spinal and epidural routes are not because of of Although ketamine is a drug of safety data regarding long-term and/or intermittent treatment are There is good evidence that ketamine in the perioperative setting reduces pain scores and opioid requirements. Adverse effects are mild or and perioperative ketamine may decrease postoperative nausea and It seems most beneficial for surgery associated with high levels of postoperative pain. 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