Pain-ALR Committee

Introduction

ketamine chronic pain is a molecule synthesized in 1962 and widely used as a general anesthetic. Today, ketamine remains the reference anesthetic agent in certain clinical circumstances, but its most widespread use is as an adjuvant to general anesthesia. Indeed, ketamine is the only potent antagonist by injection of the N-methyl-D-aspartate (NMDA) receptor available clinically to date. The NMDA receptor is known to play an important role in central sensitization phenomena. Indeed, used at low doses, ketamine has a powerful anti-hyperalgesic effect. It is used perioperatively to reduce pain and the consumption of postoperative opioids and to prevent the chronicization of pain ^{2, 4, 8, 14, 18}. Its use is gradually extending to other indications such as the management of pain in the emergency room, chronic stubborn neuropathic pain ²² , the treatment of resistant depression ^{9, 10}

Pharmacological reminder

ketamine infusion phoenix is initially an anesthetic agent present in the clinic in racemic form. The S-ketamine form, however, has a potency two times higher than the racemic form or the R (-) form and above all has fewer side effects of the psychodysleptic type, but it is not marketed in France, unlike Germany (Ketanest®). The anesthetic state induced by ketamine is characterized by deep and prolonged analgesia, a loss of consciousness which results more in a disconnection of the patient than in true sleep. The analgesic efficacy of ketamine is linked, among other things, to its blocking property of the N-methyl-D-aspartate (NMDA) receptor ³¹. From a pharmacokinetic point of view, the half-life of distribution is approximately 10 min, with therefore a rapid effect but which decreases rapidly. The elimination half-life is approximately 2 hours and increases in the event of impaired hepatic metabolism. This medicine may accumulate with repeated injections or continuous administration. Metabolism occurs through the cytochrome P450 pathway. By D-demethylation, ketamine is transformed into norketamine, the potency of which is approximately 20% that of the parent molecule.

Ketamine and hepatotoxicity

According to the Afssaps (ANSM) in a June 2010 report, there is a risk of hepatotoxicity after administration of high doses orally. On June 20, 2017, the ANSM reported cases of serious liver damage likely to be linked to the repeated and/or prolonged use of ketamine at high doses ⁴. Thus, ten cases of serious liver damage have occurred since 2014, four of which led to liver transplantation. These cases concern attacks of the cholangitis type linked to the administration of ketamine at high doses (more than 100 mg/d) continuously, repeatedly or for a long time (between 1 month and 5 months of treatment) or during painful care. repeated in severe burns (200 to 400 mg/h in 3 to 6 h). To date, there is no reason to worry and to modify our practices in the use of ketamine intraoperatively as an analgesic or as an anesthetic. The doses used in anesthesia and occasionally in chronic pain are much lower than those which cause hepatic disturbances. However, from the literature,

Regulatory reminder

Ketamine has been on the list of narcotics since April 24, 2017. Injectable ketamine preparations must follow the regulations applicable to narcotics, namely, prescription by secure prescription and traceability of entries and exits on a special register. 

Ketamine in acute postoperative pain

Evidence on effectiveness in the immediate post-operative period

Seven meta-analyses assess the benefit of ketamine therapy phoenix perioperatively, five focus on immediate postoperative effects ^{2, 4, 8, 14, 18} and two on long-term efficacy ^{5, 25} . American recommendations have just been published ³⁵. Ketamine administered perioperatively reduces morphine consumption by an average of 15 mg over 24 hours. This morphine saving is associated with a moderate 25% reduction in nausea and vomiting. No other benefit was shown on the side effects of morphine such as sedation and urinary retention. The decrease in pain intensity is significant at 6h, 12h and 24h but estimated to be low corresponding to less than 1 point on a 10-point scale, i.e. less than 30% improvement for a control group presenting an intensity of pain of 4/10. Subgroup analyzes show surgery-dependent opioid sparing. Morphine sparing is greater when ketamine is administered in painful major surgeries such as thoracic and supramesocolic surgery, morphine saving can reach 30 mg at 24 hours. Conversely, morphine saving is nil and insignificant in painless surgeries (<4/10 on the EVA), and head and neck surgery.

Evidence on immediate post-operative tolerance

The dysphoric effects of ketamine at an analgesic dose administered intraoperatively under general anesthesia are undetectable. However, they are present in 1 in 21 patients when ketamine is given to awake patients without benzodiazepines and 1 in 35 patients when benzodiazepines are given beforehand.

Evidence on long-term effectiveness

Intraoperative administration of ketamine by the IV route decreases the incidence of chronic pain by 30%. ^{5, 25} The evidence on the benefit of prolonged ketamine postoperatively in the “all comers” patient is insufficient and contradictory. ⁵ On the basis of three controlled trials, it appears that perioperative ketamine and its postoperative extension up to 48 hours is particularly beneficial in “opioid-dependent” populations ^{7, 15, 19} .

Evidence on the dosage and modality of administration

The effective plasma concentration of ketamine on analgesia is between 20 and 100ng/ml. Intravenous administration can be by bolus of 0.15mg/kg (plasma concentration between 60 and 90ng/ml) up to 0.5mg/kg, repeated boluses and/or continuous intravenous infusion 0.125 to 0.25mg/kg /h. The median dose administered in the studies is 0.4 mg/kg (0.1-1.6) ¹⁴ . Doses above 0.5 mg/kg do not provide a benefit advantage ¹⁸ . The time of administration pre or post-incision does not seem to modify the effects ¹⁸ .

What is the place of ketamine compared to other anti-hyperalgesics?

One of the questions frequently asked by the clinician is that of the comparison of anti-hyperalgesics. A comparative synthesis of the reviews of the literature on the anti-hyperalgesics used in peri-operative allows to formally answer this question. Ketamine is the antihyperalgesic of choice for the following reasons. First, ketamine is the anti-hyperalgesic with the best benefit/tolerance balance. Indeed, if ketamine and gabapentinoids have a similar benefit in terms of morphine sparing and reduction of nausea/vomiting. Gabapentinoids are responsible for an increased risk of sedation, dizziness and postoperative visual disturbances ^{13, 27}which greatly limit their use, especially in the context of outpatient care and rapid recovery after surgery. As for the analgesic benefit of magnesium, also an antagonist of the NMDA receptor, it is minimal: the morphine saving observed is weak and is not accompanied by a reduction in the side effects of morphine ^{11, 20} . Second, ketamine is the only antihyperalgesic that has shown both short-term and long-term benefit. Indeed, the long-term benefit of gabapentinoids (gabapentin and pregabalin) could not be confirmed despite a large number of studies carried out in this direction ²⁸ and the effect of magnesium on chronic pain has never been evaluated. .

Ketamine in acute pain in the emergency room and in intensive care

Ketamine is useful in facilitating painful procedures in intensive care, particularly in the pediatric population and in burn patients ^{12 16 21} . It is also useful in polytrauma patients because airway tone and reflexes are preserved and ketamine administration is not associated with reduced sympathetic tone or respiratory depression ²³ . It is increasingly used in pre-hospital ^{26 32}. Ketamine was traditionally considered contraindicated in the case of increased intracranial pressure. However, evidence from trials in TBI is conflicting and inconclusive and if there is a risk of hemodynamic instability upon induction, ketamine may still be a useful agent ^{3, 36} in this population. Ketamine can be considered in case of severe bronchospasm but the bronchodilator effect is moderate and inferior to volatile anesthetic agents. ³³

Ketamine in chronic pain

The use of ketamine in the management of intractable chronic pain is old. It stems from the physiopathological effects expected of this molecule and is based on an abundant but very heterogeneous literature in terms of dosage, duration and frequency of administration. Evidence from randomized controlled trials is strongest for intravenous administration of ketamine. The oral dosage form does not exist and there is not enough data to recommend the use of injectable ampoules, orally, especially since the evidence of efficacy is nil or insufficient in the current state of knowledge. . The two main systematic reviews on IV ketamine in intractable chronic pain find 31 randomized controlled trials with 381 patients included^{29, 30} . Short-term benefit has been reported in peripheral and central neuropathic pain and benefit over several weeks after one-time administration of ketamine has been observed in central neuropathic pain and complex regional pain syndrome ^{1, 34} . Despite the absence of Marketing Authorization in analgesia, the AFSSAPS, in the recommendations for good practice of 2010 ¹⁷, recommends the use of ketamine in stubborn pain “in an advanced palliative situation”, in combination with an opioid treatment, when the latter is insufficient or poorly tolerated; the use of ketamine in the palliative phase can also be considered for pain treatment, after failure of the usual therapies (opioids, MEOPA), and if general anesthesia in an operating theater cannot be organized. Finally, national surveys report that ketamine is frequently used off-label to treat stubborn chronic pain ²⁴. Several studies in France are in progress (OKAPI, KETAPAIN, KEKU and LIKE studies (registered on clinical trial) in order to specify the practical methods of use, the effective dosages and the profile of responding patients. American formalized consensus recommendations on the he use of ketamine in chronic pain was just published in July 2018 and defines its indications and the conditions for its administration ⁶. The following common-sense rules follow: 1°) The indication to continue treatment with ketamine must be based on an improvement in the patient’s pain and/or quality of life of more than 30% at middle term ; this assessment must be recorded in the patient’s medical file; 2°) In all cases, the benefit of continuing repeated administrations of ketamine over the long term must be regularly reassessed (for example in a multidisciplinary consultation meeting) with traceability in the medical file; 3°) It is recommended to carry out a liver test regularly during repeated administrations of ketamine.

Findings:

Ketamine, the only potent antagonist of the N-methyl-D-aspartate (NMDA) receptor available in the therapeutic arsenal, represents the anti-hyperalgesic of choice with the best benefit/tolerance balance. Indeed, data from the literature confirm its efficacy when used intraoperatively (at a dosage < 0.5 mg/kg) in the event of thoracic or supra-abdominal surgery, in the event of severe postoperative pain and particularly in people vulnerable” to pain. It allows significant morphine saving as well as a moderate reduction in the incidence of nausea and vomiting. In addition,