How does ketamine affect the hippocampus

Ketamine: Use for chronic pain and depression

Summary

Although ketamine has been known for a long time and is in clinical use, questions about the various possible fields of application as an anesthetic and analgesic still remain open. These do not relate to the classic area of ​​application in emergency medicine and anesthesia, but also to potential, new indications in which ketamine is used in low, sub-anesthetic doses. The mechanism of action at the NMDA receptor clearly distinguishes ketamine from all other analgesics. Possible areas of application are the prevention of chronic postoperative pain and the treatment of neuropathic pain. With the treatment of refractory depression, ketamine could also establish itself in an entirely new field.

Summary

Although ketamine has been known and clinically applied for a long time, questions still arise around the many possible indications in which the anesthetic and analgesic substance could be used. In particular, these questions relate to new indications in which ketamine is used in low subanesthetic doses.

The mechanism of action at the NMDA receptor clearly distinguishes ketamine from all other analgesics. Possible applications include the prevention of chronic postoperative pain as well as the treatment of neuropathic pain. With the treatment of refractory depression completely new therapeutic areas for ketamine could be established.

introduction

The anesthetic and analgesic ketamine, developed in the 1960s, was mainly used in accident and emergency medicine for over 50 years, as it allows rapid pain relief through to deep anesthesia without the risk of respiratory depression. Meanwhile, however, there is also increasing interest in ketamine in low, non-anesthetic doses. Potential indications here are the perioperative use to prevent hyperalgesia and chronic postoperative pain as well as the treatment of chronic pain [1, 4] and therapy-resistant depression [2, 4]. How the evidence and case reports for ketamine are presented in these areas of indication, and which treatment recommendations can be derived from them, is the subject of the following review.

Properties of ketamine

Ketamine is a chiral derivative of cyclohexanone with a stereocenter and belongs to the arylcyclohexylamine family. It is structurally related to numerous other anesthetics and psychoactive substances such as methoxetamine (MXE) or phencyclidine (PCP). Ketamine was introduced in 1962 and is considered a “dissociative anesthetic” due to its combination of psychotropic and analgesic effects [1,2,3].

Pharmacokinetics and Forms of Use

Ketamine is metabolized in the liver via the cytochrome P-450 system, presumably via CYP 3A and CYP 3A 4, CYP 2B6 and CYP 2C9, and excretion via the kidneys is minimal. However, not all questions have been answered here. While the inhibition of CYP 3A, for example by clarithromycin or grapefruit juice, increases exposure after ingestion of oral S-ketamine, the CYP 3A4 inhibitor itraconazole should not interact with S-ketamine. The potent CYP 3A inducers rifampicin and St. John's wort reduce the plasma levels of S-ketamine very significantly after oral administration, but much less after intravenous administration.

The metabolites are pharmacologically active, with norketamine (metabolite I) until recently considered to be the most important metabolite. However, the importance of norketamine is currently being questioned. Although ketamine is relatively rapidly converted to norketamine N ‑ demethylated, norketamine itself is likely to be further metabolized to 6 ‑ hydroxynorketamine more rapidly than previously assumed and is not the most important metabolite in plasma. Norketamine has about a third of the anesthetic effectiveness of ketamine. The half-life of ketamine in the beta phase is around 2.5 to 3 hours, the rate of excretion is likely to depend on the blood flow in the liver [1, 3].

Intravenous injection / infusion

Both racemic ketamine and S-ketamine are in use. A recent review indicates, however, that S ‑ ketamine is likely to be easier to titrate because it has a higher clearance and a steeper increase in the effect with concentration (concentration – effect curve) and the absence of the R enantiomer avoids metabolic interactions. In anesthesia, S ‑ ketamine i.v. Induction doses of 0.5–1.0 mg / kg, followed by repeated maintenance doses of 0.25–0.5 mg / kg (bolus) or continuous infusion of 0.5–3.0 mg / kg / h are recommended. In analgesic use, the bolus doses are 0.1–0.25 mg / kg, followed by continuous infusion of 0.2–1.0 mg / kg / h. When using racemic ketamine, these dosages have to be doubled. After intravenous application of ketamine there is an initial surge (alpha phase) with a half-life of ten to 15 minutes and a total duration of approx. 45 minutes [3].

Oral ingestion

The bioavailability of oral ketamine is poor due to a pronounced first-pass metabolism. Only around 17–24% of oral racemic ketamine and 8–11% of oral S ‑ ketamine reach the systemic circulation. Due to the metabolism in the liver, after oral intake of S ‑ ketamine, much more S ‑ norketamine than ketamine enters the circulation. A steady state of oral S-ketamine is reached after the third dose; there is no accumulation of S-ketamine or its metabolites when S-ketamine is taken orally twice daily [5]. Since S ‑ norketamine is a weaker analgesic than S ‑ ketamine, it is estimated that the dose must be increased by a factor of 2.4 when taken orally compared to intravenous in order to achieve the same AUC (area under the curve) [3 ].

Intramuscular injection

Ketamine can also be injected intramuscularly. This leads to rapid absorption with a bioavailability of 93%. Ketamine can be detected in the plasma after just four minutes, and peak concentrations are reached after five to 30 minutes. It starts to work just one to five minutes after the injection. Due to the rapid onset of action, the i.m. Injection is an alternative to intravenous administration if no suitable intravenous access is available [3].

Sublingual application

Sublingual formulations of ketamine are under development as user-friendly options for third-line therapy for pain patients. The bioavailability is no better than when taken orally. However, the metabolism to norketamine is less pronounced and the maximum plasma level (Cmax) is reached more quickly (0.5 vs. 2 h). Sublingual administration can be advantageous if a rapid effect is sought, which can be the case with acute pain or breakthrough pain in oncological pain therapy [3, 6, 7].

Nasal application

Intranasal administration of ketamine bypasses first pass metabolism in the liver. This means that the metabolism to norketamine remains low. At around 45%, the bioavailability of nasal ketamine is slightly better than when taken orally. Cmax is achieved with ketamine nasal spray ten to 17 minutes after application, which leads to a faster onset of action than with oral, sublingual or rectal administration. The rapid onset of action makes nasal ketamine an option in the treatment of breakthrough pain, but the exact dosage is difficult to control [3].

Rectal application

With rectal application, similar bioavailability and AUC of norketamine are achieved as with sublingual ketamine. Rectal administration can be an option for patients who are unable to swallow [3].

How ketamine works in the central nervous system

The pharmacological effect of ketamine is based on the non-competitive inhibition of the N-methyl-D-aspartate subtype of the glutamate receptor (NMDA). This means that ketamine has a unique mechanism of action among anesthetics and analgesics. NMDA receptors are involved in various processes that contribute to the development of chronic pain. Among other things, they play an important role in the process of central awareness raising [8]. This makes ketamine an obvious option to prevent pain from becoming chronic.

However, there are also a number of other effects on numerous other receptors. This subheading includes the tonic blocking of voltage-independent NA channels (resulting in a local anesthetic effect), the blocking of acetycholine receptors (bronchodilatory effect) and, in high doses, the opiate receptor (δ, µ) mediated effects that lead to a potentiation of the opiate effect . S ‑ ketamine shows two to three times more affinity for opiate receptors than R ‑ ketamine. However, naloxone does not affect the effects of ketamine in humans. The contribution of the opiate receptor to the effect of ketamine is therefore likely to be limited.

Furthermore, ketamine acts via the AMPA receptor and metabotropic glutamate receptors (mGluR) as well as L-type Ca2 + channels and causes an increase in the release of dopamine and norepinephrine. In addition to these immediate effects, there are delayed effects, namely the inhibition of IEG (immediate early genes) expression (c-fos, c-jun) as well as the activation of astrocytes and microglia and thus possibly also an influence on the neuroimmune interaction. Ketamine also modulates the phosphorylation of the NMDA receptor [9].

Clinical effects of ketamine

These complex mechanisms of action result in a wide range of clinical effects and areas of application. Ketamine combines analgesia and rapid sedation in one substance, with analgesia being in the foreground at low doses [1, 3]. The literature often defines a low dose as a bolus of less than 2 mg / kg intramuscularly or 1 mg / kg intravenously [10]. In relation to S - (+) - ketamine, a maximum of half of these values ​​is recommended as a low dose.

In low doses, ketamine has an antihyperalgesic, antiallodynic and tolerance-protective effect. As additional, potentially desired effects, there are also anticonvulsant, antidepressant, anti-inflammatory and neuroprotective effects. Ketamine thus has a wide range of potential areas of application. It affects the hemodynamic stability just as little as the intestinal motor function and does not cause respiratory depression even in higher doses.

This results in numerous potential areas of application in pain medicine - but also beyond. Ketamine can be used preclinically in emergency medicine, as well as intraoperatively and postoperatively to prevent chronic postoperative pain. Further possible areas of application are the therapy of chronic pain and sedoanalgesia in the intensive care unit, whereby the neuroprotective effect is also used [1, 3].

While the use of ketamine as a single substance or in an anesthetically effective dose for general anesthesia has become rare today because of undesirable psychotropic effects, but remains an option for hemodynamically unstable patients, numerous randomized, controlled studies on the use of ketamine in published sub-anesthetic doses in the treatment of acute and chronic pain conditions. The newly awakened interest in the substance also has to do with the fact that the (S) -enantiomer (S) -ketamine has been available since the late 1990s, which is four times more analgesic than (R) -ketamine . The studies show, among other things, that ketamine in analgesic doses does not show the undesirable side effects of high doses or only shows them to a very limited extent [1,2,3,4].

Prevention of post-operative pain and opioid-induced hyperalgesia

One of the well-studied areas of application is the prevention of acute postoperative pain through the use of low-dose ketamine in perioperative pain management [11].

The NMDA antagonist ketamine is interesting in this context, as opioids in high doses, despite their strong analgesic effect, cannot prevent central sensitization during surgery and the resulting postoperative hyperalgesia, but can even intensify it. In the animal model, an effect not only on C-fiber evoked potentials but also on long-term synaptic potentiation (a form of synaptic plasticity) was demonstrated for low-dose (S) -ketamine [12,13,14].

There is also extensive data on use in humans. For example, postoperative hyperalgesia could be demonstrated after major abdominal surgery if higher doses of remifentanil were used intraoperatively. This effect did not occur with the combination of remifentanil and ketamine, as with the use of lower remifentanil doses. This makes ketamine an alternative to increasing the dose of the opioid [15]. A systematic review of randomized, controlled studies found clear indications of the reduction of postoperative hyperalgesia by the perioperative administration of intravenous ketamine, whereby the effect was independent of the time of fentanyl administration, the type of opioids used and the ketamine dose [16]. The use of low-dose ketamine in combination with epidural analgesia (and general anesthesia) in open laparotomies for rectal cancer was investigated. In the follow-up up to 12 months it was shown to be very effective, also in preventing pain chronicity [17].

Detailed recommendations for the peri- and intraoperative use of (S) -ketamine were published in 2005 [18]. A relatively recent review shows that the use of low-dose ketamine reduces the perioperative need for opioids by 40% without this advantage being bought at the cost of serious side effects [19]. A typical bolus dose of ketamine is 0.15 mg / kg, the infusion rate can vary between 0.15 and 1.2 mg / kg / h, and the duration of treatment is between two and 48 hours. When the cumulative dose is kept low, side effects (especially psychotropic) are usually minor [3, 5].

The background to the reduction in the postoperative opioid requirement through the perioperative use of ketamine should not only be the influence of the NDMA antagonist on the central sensitization. Rather, experiments in animal models suggest that ketamine prevents the acute development of tolerance to opioids. At least in rats, very low doses of ketamine are sufficient, which alone do not suggest an analgesic effect [20].

Anti-inflammatory effects (including a reduced production of the cytokines TNF-alpha and interleukin 6) may also be involved in the prevention of postoperative hyperalgesia caused by ketamine [21].

A recent interdisciplinary position paper on perioperative pain management [11] recommends using ketamine as part of multimodal perioperative pain management in major interventions if there are no contraindications.

Ketamine has been shown to be helpful in treating opioid-resistant acute post-operative pain. In a controlled study, co-administration of a single, low dose of ketamine and morphine substantially reduced severe postoperative pain. In this study, ketamine also improved the analgesic effect of further morphine administration [22]. A possible explanatory model for this is provided by experiments in animal models, which show that co-administration of morphine and ketamine increases the concentrations of both substances in the brain and ketamine can also influence morphine tolerance [23].

A feared and unfortunately not uncommon complication of various surgical interventions is the chronification of postoperative pain, which - depending on the procedure and patient population - affects up to 50% of patients [17, 24].

Prevention of chronic postoperative pain is particularly important in patients at risk, i.e. chronic pain patients, patients receiving opioid therapy and those with a high intraoperative need for opioids. Amputations, thoracotomies, mastectomies and possibly also hernia operations are considered to be particularly risky operations [25]. Other risk factors for persistent, postoperative pain include women, younger age, preoperative pain, postoperative pain, reduced inhibition of noxious stimuli (conditioned pain modulation, CPM), psychosocial predictors, genetic disposition and intraoperative nerve damage.

Whether ketamine can reduce the risk of developing chronic, persistent postoperative pain is under discussion. A review article published in 2016 [3] lists evidence for and against. On the one hand, a meta-analysis found substantial reductions in persistent postoperative pain due to perioperative intravenous ketamine [26]; on the other hand, this could not be confirmed in two recent randomized, controlled studies for post-thoracotomy pain [27, 28].

In this indication, ketamine may therefore be an option for certain patient groups and certain interventions that need to be identified in further studies. A recent Austrian position paper on perioperative pain management emphasizes the importance of ketamine in the context of amputations [11].

Ketamine for chronic pain

Chronic Pain Treatment

Another special feature of ketamine is its effectiveness against neuropathic pain. This is attributed to the importance of the NMDA receptor in the genesis of neuropathic pain [29].In addition, however, there is also evidence that ketamine influences the descending pain inhibition and has anti-inflammatory effects. Indications of an effect of ketamine in sub-anesthetic doses on mechanisms of decreasing pain inhibition were demonstrated by means of functional MRI. Study data also suggest that these effects not only occur in healthy volunteers but also in patients with small fiber Neuropathy may occur. Ketamine could therefore help restore physiological pain inhibition in patients with neuropathic pain [30, 31].

One controlled study compared the effectiveness of ketamine in treating neuropathic pain with both methadone and the combination of ketamine and methadone. The ketamine monotherapy proved to be superior in comparison to the two other arms, which was due to the better effect of ketamine on the symptom of allodynia [32].

The effect of ketamine on chronic pain, especially when it has a neuropathic component, has been demonstrated in a large number of studies. However, a review [33] states that most of these studies do not provide any practical information because they examined ketamine infusions and thus often only had an effect that was limited to a few hours. Long-lasting pain reduction was seen in several studies when the ketamine infusion was extended over a period of several days. In chronic, therapy-resistant complex regional pain syndrome (CRPS), infusions of analgesic ketamine doses over several days resulted in an improvement in pain symptoms lasting up to three months [34]. The review emphasizes, however, that no reliable long-term data are available on the use of ketamine in chronic pain [33]. Another review from 2016 points to the extremely heterogeneous data situation on the use of ketamine in pain therapy. In the studies on the use of oral ketamine, for example, the duration of treatment was between a single dose and continuous therapy over 660 days. In most of the studies, treatment was given for between 20 and 80 days. The dosages used also range from very low oral doses to 62.5 mg / kg / d. The authors emphasize that they could not identify a dose-response relationship. While oral ketamine was effective in minimal doses in some papers, other papers found no analgesic effect with high intravenous doses. However, a dependency of the side effects on the dose was found. The often described severe neurological and urological complications in connection with chronic ketamine abuse are only to be expected after prolonged consumption of very high doses, which are well above the usual analgesic doses [4].

Case series data indicate that ketamine is effective in treating chronic, therapy-resistant migraines. With low-dose ketamine infusions, a marked improvement in symptoms was achieved with good tolerability in those affected over at least eight hours [35]. Long-term data are still missing here as well.

Similar experiences were reported in a recently published case series with patients with refractory migraines or chronic headache (new daily persistent headache - NDPH). The 77 patients received infusions of low-dose ketamine over a longer period of time - on average 4.8 days after various unsuccessful (also inpatient) therapy attempts. This resulted in a significant improvement in the symptoms. Patients experienced pain on admission with a magnitude of 7.1 on a pain scale of zero to ten. On discharge, the pain had decreased to an average of 3.8 (P. <0.0001). Of the total of 77 patients, 55 (71.4%) were classified as responders. Of these 55 responders, the effect persisted in 15 (27.3%) until a further control visit, but this advantage was not statistically significant. The authors emphasize that ketamine was well tolerated and call for controlled studies [36].

Ketamine and cancer pain

The use of ketamine in oncological pain patients is of particular interest where the pain has a clear neuropathic component and has been investigated in several open studies. Good pain relief was found in around 70 to 80% of patients. However, adequate analgesia cannot be achieved in ten to 30% of patients [37].

In a case series with young cancer patients, the use of ketamine as an adjuvant resulted in a reduction in the opioid dose in eight of eleven patients [38]. In contrast, a randomized, placebo-controlled study found no beneficial effect for the use of subcutaneous ketamine as an adjuvant to opioid therapy. In this setting, ketamine was not found to be superior to placebo, but it did develop substantial side effects [39]. Because of this work, the use of ketamine in oncological pain therapy was largely abandoned for a few years. It is only recently that there has been new interest. A review published in 2015 came to the conclusion that ketamine is an interesting option in the treatment of cancer pain that no longer responds to opioids. The authors emphasize, however, that the evidence on the use of ketamine for cancer pain is by far less than that for non-oncological pain. Most of the studies identified were small, often methodologically weak and overall very heterogeneous, but the majority found beneficial effects from the use of ketamine in cancer pain that is difficult to control. Oral application seems to be more tolerable than parenteral [40].

With this in mind, the Palliative Care Guidelines of the European Society for Medical Oncology (ESMO), based on a systematic review of the literature, recommend the use of ketamine for the palliative treatment of patients with neuropathic pain in an oncological setting. This treatment should be carried out under the guidance of specialists. It is also recommended for complex neuropathic and vascular pain syndromes in which opioids have lost their effectiveness. Basically, according to ESMO, ketamine should only be used when combinations of oral opioids and adjuvant analgesics have become ineffective. Delirium, seizure disorders or psychosis are contraindications [41]. In the case of increased intracranial pressure, there is a contraindication if the patient is spontaneously breathing.

An algorithm used at the Vienna Wilhelminenspital shows what the use of ketamine in oncological pain therapy can look like in clinical practice [42]. It is used in patients with therapy-resistant pain despite exhausting all analgesic options and takes into account the individual very different responses to ketamine and the individual side effect profile. The patient initially receives a test dose of 5–10 mg S-ketamine as a short infusion. If this does not have any effect or if there are significant side effects (mostly psychotropic), no further ketamine doses are given. Responders who achieve good analgesia with minimal side effects continue to be treated with ketamine in intravenous or oral form. The use of ketamine in the pain pump is also an option, with the hope that the early combination of opioids with ketamine dose escalations can prevent tolerance development. Candidates are patients with a need for morphine (pump or IV) of more than 200 mg per day.

Attempts to treat chemotherapy-induced peripheral neuropathy with topical ketamine / amitriptyline proved ineffective in a controlled study [43].

Ketamine in the treatment of depression

Low-dose ketamine is currently being researched and discussed as a novel, fast-acting antidepressant. The literature contains evidence of a rapid antidepressant effect of low-dose intravenous ketamine in "major" depression, in bipolar depression and in depression with suicidal ideation. The suspected mechanisms of action of ketamine differ significantly from those of other antidepressant substances and also go beyond the known ketamine effect on the NMDAR. In the animal model, for example, ketamine was linked to mTOR (mammalian target of rapamycin) -dependent synapse formation in the prefrontal cortex of the rat, eukaryotic elongation factor 2 (p-eEF2) phosphorylation and glycogen synthase kinase (GSK-3) brought. In this indication, too, the limiting factor seems to be the transient nature of the antidepressant effects of ketamine. There are also concerns about abuse and addiction [44].

A randomized, controlled study with a single infusion of ketamine compared to an active placebo control with the anesthetic midazolam showed how clear the antidepressant effect can be. Included were patients with treatment-resistant depression during a depressive phase. In this setting, ketamine showed a rapid antidepressant effect and was well tolerated. Dissociative symptoms occurred in 17% of the patients, but after seven days there was no longer any difference between the groups in this regard [45]. Here, too, there is a lack of information on response duration and safety, which would be required before implementation in clinical practice. The effectiveness of oral ketamine in treatment-resistant depression has also been documented in case reports [46]. An open pilot study that examined the influence of daily oral ketamine on anxiety and depression in 14 hospice patients also produced promising results and found an excellent response over a period of four weeks [47].

Of particular interest is the effect of ketamine, documented in studies, on the symptom of anhedonia, which is particularly stressful for the patient and can hardly be influenced by conventional drug therapies. A randomized, placebo-controlled study with 36 patients with therapy-resistant bipolar depression was able to show that a single ketamine infusion can significantly reduce the anhedonia level over the entire observation period of 14 days [48].

In an open study, the same group with a ketamine infusion achieved a significant reduction in anhedonia in patients with unipolar depression. It could also be shown that the improvement in anhedonia is associated with increased glucose metabolism in the hippocampus and in the dorsal anterior cingulate gyrus (dACC) as well as reduced metabolism in the inferior frontal gyrus and the orbitofrontal cortex (OFC) [49].

Several recent reviews allow a better classification of the possible role of ketamine in the treatment of unipolar and bipolar depression. However, this work also shows how limited the data situation is at the present time. A review based on a data search on EMBASE, PsycINFO, CENTRAL and Medline for the period from 1962 to January 2014 found seven randomized controlled trials on the use of intravenous and one for nasal ketamine in the treatment of major depressive episodes. A total of 73 patients in parallel group studies and 110 patients in crossover studies were included in these studies. Ketamine proved to be superior to the comparator arm at all times examined (24 hours to seven days). The effectiveness was better in unipolar depression than in bipolar depression. Ketamine was shown to be associated with transient psychotomimetic effects, but did not lead to persistent psychosis or an affective switch [50]. Another review highlights the increasing off-label use of ketamine in psychiatric indications. For example, ketamine infusions are increasingly being used as a substitute for electroconvulsive therapy (ECT) in refractory depression. The combination of ketamine and ECT, on the other hand, has proven to be incompatible and ineffective [51]. Regardless of the documented successes, there are still numerous unanswered questions. This applies in particular to the dosage and strategies that make long-term antidepressant treatment with ketamine possible [10, 52].

In this situation, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments recently issued a consensus statement on the use of ketamine in psychiatry [53]. The authors emphasize that this use is basically off-label and the evidence behind it is very limited. In general, it is only possible to give recommendations for the treatment of severe depression without psychotic symptoms, since the data are currently too thin for all other indications. This document also points out that the available data come mainly from studies with a maximum observation period of one week after a single infusion of ketamine and that the effects of repeated ketamine administration have only been investigated in a few studies [54, 55]. Although such regimes are used in several centers, there are so few published results that no evidence-based recommendations can be made.

The consensus states that patients must be carefully clarified and informed before treatment with ketamine. Informed consent must form the basis of treatment. This must be carried out at a center that has the facilities for cardiovascular monitoring and the necessary interventions in the event of complications. The center must also be prepared for the possibility of a psychotic reaction from the patient. The study situation is heterogeneous with regard to dosage and route of administration; the intravenous infusion of 0.5 mg / kg over 40 min has been the best studied.

Abuse Potential and Side Effects

In terms of side effects, the psychotropic effects of ketamine are of particular concern - especially when taken for a long time. In healthy people, an acute dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine can induce marked psychosis-like effects and cognitive impairments. Ketamine also has potential for abuse.

Ketamine side effects are usually dose-dependent and spontaneously reversible [56]. It should be noted that ketamine is used for the treatment of chronic pain or depression in doses that are well below the anesthetic dose. The therapeutic breadth makes it a safe drug [26].

Side effects of ketamine, especially in anesthetic doses, include an increase in heart rate and arterial blood pressure, as well as an increase in myocardial oxygen consumption. Because of these effects, arterial hypertension, heart diseases such as chronic heart failure, heart defects or coronary heart disease are absolute contraindications for the use of ketamine. Likewise, poorly controlled hyperthyroidism or aneurysms speak against the use of ketamine. Recent studies speak against the discussed concerns that ketmin could increase intracranial pressure [57]. Glaucoma, a history of mental illness or epilepsy, porphyria or use in the first trimester of pregnancy are contraindications [58,59,60].

The respiratory depressive effect of ketamine is only slight, the relaxing effect on the bronchial muscles can break through an asthma attack. The intraocular pressure is increased by ketamine, as is the tone of the uterine muscles. Hypersalivation and increased bronchial secretion are further side effects of ketamine [information for healthcare professionals]. The additional use of sedatives to reduce psychological side effects increases the risk of respiratory depression.

Chronic use of ketamine can lead to damage to the urogenital tract, which is reversible with abstinence. These include pain in the urinary bladder, incontinence or papillary necrosis [60].

As far as the psychoactive properties of ketamine are concerned, dissociative symptoms, hallucinations, dysphoria, anxiety or disorientation can also occur in sub-anesthetic doses.

In view of the central effectiveness of ketamine, caution should be exercised with other psychoactive substances such as alcohol, opioids, benzidiazepines, cannabis and cannabinoids [56].

The widespread "recreational use" of ketamine among young people provides some data on long-term side effects. A large number of psychiatric and neurological complications have been described in connection with chronic ketamine use. Overdose deaths are rare and are usually related to the use of other psychoactive and / or sedating substances such as alcohol. Injections of ketamine doses far in excess of the usual anesthetic doses were survived without any consequential damage [61, 62].

In an epidemiological study, frequent ketamine users, rare ketamine users, abstinent users, polytoxicomaniac controls and non-users of illegal drugs were compared over a year. The study found cognitive deficits and increasing ketamine consumption in the group of frequent users in connection with decreasing performance with regard to spatial working memory and a deterioration in pattern recognition memory tasks. The assessment of psychological well-being showed more dissociative symptoms in “frequent users” and a dose-response effect on delusional symptoms, with higher scores in “frequent users” than in rare, abstinent users and non-users. Both “frequent users” and the abstinent group showed increased levels of depression over the 12 months [63].From these data it can be deduced that heavy use of ketamine has adverse effects on both cognitive function and psychological well-being. To what extent this also applies to the medically indicated use of ketamine, or to what extent the abuse potential and psychotropic side effects of ketamine can be controlled, studies have to show.

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