Through ketamine fields
Viana Chaves, Tharcila
DOI:10.33612/diss.107955714
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Publication date: 2019
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Viana Chaves, T. (2019). Through ketamine fields: pain and afterglow. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.107955714
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Chapter 7
General discussion
In this thesis, different angles were used in order to understand the history, the medical applications, and the negative side of the use of ketamine in medicine. Inevitably, the discussion around the recreational use of this drug was also an important point, considering that it is a popular drug of abuse and the concern about the development of drug dependence is a major public health issue.
The first chapter gave an introduction about psychedelic medicine and the relevance of ketamine in this field. The hedonistic use of ketamine associated with an emerging (now very well established) dance culture was also worthy of mentioning in the introductory chapter. A study performed in 31 nightclubs of Sao Paulo, Brazil, using a mixed-method design, collected two levels of information: observational data and in loco survey data. Individual-level data were collected by a in loco survey with 2,422 subjects at the entrance and 1,822 subjects at the exit. Interestingly, data triangulation has shown an association between lower alcohol consumption and ketamine use in three LGBT (i.e. lesbian, gay, bisexual and transgender) nightclubs (1). More about recreational polydrug use was discussed in chapter 6.
The second chapter presented a thorough analysis of the scientific literature concerning the management of pain and treatment-resistant depression (TRD) with ketamine, which provided a great frame about routes of administration, dosages, safety, and adverse effects. This chapter concluded that ketamine appears to be well-tolerated, even though few studies have systematically examined the long-term consequences of repeated doses of ketamine. This is a point of concern because the analgesic and antidepressant effects of ketamine are not permanent, requiring the patients to have multiple doses in order to keep themselves relieved from pain and/or depression symptoms.
On this matter, an open-label study performed at the Mount Sinai School of Medicine (New York, United States) with ten patients with TRD applied repeated ketamine intravenous (IV) infusions over the course of two weeks. In total, six infusions were applied in eight patients (one patient did not meet response criteria at 24 hours after the first infusion and was eliminated from the study; one patient missed the fourth infusion). The 40-minute continuous infusion at a 0.5 mg/kg dose was well-tolerated; no patient reported greater than mildly bothersome side effects at any time. The observed vital signs changes were transient and did not warrant treatment cessation (2). Caution regarding long-term cognitive impairment caused by repeated ketamine administration demands more studies with long follow-ups and larger sample sizes.
Despite its unpopularity, electroconvulsive therapy (ECT) is still widely used for treating some mental disorders, such as TRD. In a comparison with ketamine, Messer et al. (2010) selected two adult patients with major depressive disorder (MDD) without psychotic features, who had received multiple ECT treatments and had persistent symptoms of depression. They were hospitalised for a twelve-day study
period with a series of ketamine infusions. In their medical record, one of the patients had passed through seven ECT sessions and the other through 105 sessions. Both participants had marked changes in depression symptoms in response to ketamine treatment, as measured by the Beck Depression Inventory. No cognitive impairment was observed, as well as no difficulties with memory, no respiratory suppression, and no problem with heart rate. The ketamine infusions were not associated with short-term memory loss or confusion, which can be significant problems caused by ECT. The patients reported more immediate recovery and a marked change in mood, which they did not experience with ECT (3).
The effects of ketamine in patients with MDD referred to ECT were also studied by Kranaster et al. (2011) and Loo et al. (2012). The first compared a group who received ECT treatment with ketamine (n = 16) or thiopental (n = 26); the ketamine group needed significantly fewer ECT sessions and had significantly fewer depressive symptoms afterwards (4). The latter performed a randomised controlled trial (RCT) with 51 depressed patients; they were randomised to receive either ketamine or placebo (saline) in addition to thiopentone during anaesthesia for ECT. Ketamine was safe and slightly improved the efficacy in the first week of treatment and at one-week follow-up (5).
In chapter 3, the question about why ketamine is still not approved for pain and depression treatments is raised. This article was published in 2017. Since then, the number of ketamine clinics in the United States has been rising, making it an accessible treatment for the general public, despite the still unsolved situation with health insurances, who deny the refund because it constitutes an off-label use of a drug. Furthermore, in March 2019, an intranasal spray of esketamine has been approved by the United States Food and Drug Administration (FDA) for TRD. Antidepressant ketamine has made its way to conventional medicine.
Noteworthy, the first clinical trial on the antidepressant effect of ketamine was published in 2000 by Berman et al. (6). In this study, seven subjects with depression completed two test days that involved IV infusions with ketamine hydrochloride at 0.5 mg/kg or saline under randomised double-blind conditions. Subjects evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion, suggesting a potential role for N-methyl-D-aspartate (NMDA) receptor-modulating drugs in the treatment of depression (6). In the subsequent years, science has been confirming this potential, as presented and discussed in this thesis.
In regard to safety, ketamine was successfully tried on American soldiers in the Vietnam War because it could be administered by a corpsman or a fellow soldier due to its relative safety and ease of administration. Soldiers could inject ketamine in wounded buddies by the intramuscular route in a secure way in the knowledge that they would probably not stop breathing as a result of the anaesthetic; that
is when ketamine got nicknamed “the buddy drug”. It became the most widely used battlefield anaesthetic, sedative and analgesic, giving an excellent opportunity for American anaesthesiologists and surgeons to become familiar with this drug. The use of ketamine during battlefield-casualty evacuations helped to decrease the mortality rate of wounded soldiers who made it to medical treatment from 4.5% during the Korean War to 2.6% during the Vietnam War. The American soldiers in the Vietnam War knew that if they were wounded, they had a better chance of surviving than in any other war, a fact that did much to boost troop morale (7-9).
In emergency medicine, the use of ketamine prior to the 1990s was infrequent. However, after a landmark study by Green and Johnson (1990), it has become one of the most prevalent agents for procedural sedation and analgesia. In their review of 11,589 administrations of ketamine for sedation, Green and Johnson (1990) firmly established ketamine’s safety and efficacy for medical use (10). Today, ketamine remains among the most popular general anaesthetics, especially in the “developing world” and emergency contexts, because of its low cost, ease of storage, advantageous airway and respiratory properties, haemodynamic stability, broad range of clinical applications, and excellent therapeutic index. Ketamine’s wide therapeutic window makes it the anaesthetic of choice in resource-poor environments where monitoring equipment may be rudimentary or absent (8, 11, 12).
The examination of the discourses of a diverse sample of ketamine users, the development of addiction, and harm reduction were core points of chapter 4. This qualitative investigation brought many underground knowledge into light. Nowadays, the internet is the most popular channel to exchange harm reduction tips and strategies. Also, it is a great source of new trends of drug use. The accuracy of the information analysed in the Bluelight reports confirms that access to information is essential. Once information is available, people tend to explore it, discuss it and share it, contributing enormously to an educated drug consumption.
The essential feature of substance dependence is a cluster of cognitive, behavioural, and physiological symptoms indicating that the individual continues using a substance despite significant substance-related problems. There is a pattern of repeated self-administration that usually results in tolerance, withdrawal, and compulsive drug-taking behaviour (13). The harm reduction philosophy accepts the evidence that many people will continue to take drugs even when they are fully aware of all the dangers involved. In the 1983 book “From chocolate to morphine: understanding mind-active drugs”, Weil and Rosen state: “There are no inherently good or bad drugs, just good or bad uses” (14). Sessa (2015) adds: “Many modern activities can be either dangerous or safe, including bungee-jumping, playing squash, horse-riding, taking prescribed drugs, drinking beer, having sex, and crossing the
road. They can all be dangerous but can also be relatively safe if done moderately and with care and attention” (15). Every drug currently marketed in any part of the world has side effects. The role of health care professionals is to monitor each patient closely and check if a specific treatment is being effective, deleterious or useless.
In chapter 5, the concept of central sensitisation was presented, as well as how ketamine can be useful in attenuating the pain caused by this condition. As in depression, it seems that the blocking of NMDA receptors is responsible for the analgesic effect of ketamine. Interestingly, chapter 5 provided a reflection about the connection between body and mind, explaining the overall relief from mental and physical pains produced by ketamine.
It is clear that ketamine has a wide range of applications in medicine. Besides the aforementioned ones, ketamine has been used as a neuroprotective agent to prevent brain damage from head trauma, strokes, heart attacks, epileptic seizures, low oxygen and blood-sugar levels (8, 16, 17). Moreover, ketamine has been showing positive results in the treatment of alcohol dependence. Subanaesthetic doses of ketamine are not rewarding (18) and some studies have shown that recently detoxified alcoholics given ketamine did not go back to their alcohol consumption (19, 20). Also, for cocaine dependence, ketamine seems to produce positive results. Dakwar et al. (2019) reported that a single ketamine infusion in 55 cocaine-dependent individuals, coupled with a mindfulness behavioural modification programme, promoted abstinence and reduced the risk of relapse. Subjects were randomly assigned to receive a 40-minute infusion of ketamine or midazolam (as the control group; midazolam has no known effect on cocaine dependence) during a five-day inpatient stay. All participants began a mindfulness-based relapse prevention programme in the hospital, which continued in four weekly outpatient sessions. During the last two weeks of the five-week trial, 48.2% of the ketamine group were abstinent compared with 10.7% of the midazolam group. The ketamine group was 53% less likely to drop out of the study or relapse compared with the midazolam group. This study also suggests that ketamine may help patients gain more benefit from behavioural interventions by reducing cravings, increasing motivation, and dampening reactivity to high-risk situations.
Ketamine can also be a precious tool in managing postoperative pain in opioid-dependent patients with chronic pain. Considering that the use of opioids for the control of chronic pain is now commonplace, the number of patients developing opioid tolerance and dependence is following this trend. Opioid prescriptions increased greatly over the past decade, with hydrocodone/acetaminophen being the most commonly prescribed drugs in the United States for the past several years by a substantial margin. Once the field of the pain specialist, long-term opioid prescribing is now in the repertoire of most primary care physicians and almost all chronic pain management guidelines endorse the use of opioids at some point in chronic pain treatment protocols (21-23).
Moreover, Loftus et al. (2010) conducted a randomised, prospective, double-blinded, placebo-controlled trial involving opiate-dependent patients undergoing major lumbar spine surgery. Fifty-two patients in the treatment group were administered 0.5 mg/kg IV ketamine on induction of anaesthesia and a continuous infusion at 10 µg/kg/min was begun on induction and terminated at wound closure. Fifty patients in the placebo group received saline of equivalent volume. Patients were observed for 48 hours postoperatively and followed up at six weeks. Total morphine consumption was significantly reduced in the treatment group at 48 hours after the procedure. It was also reduced at 24 hours and at 6 weeks. The average reported pain intensity was significantly reduced in the post-anaesthesia care unit and at 6 weeks. This study indicates that intraoperative ketamine reduces opiate consumption in the 48-hour postoperative period in opiate-dependent patients with chronic pain. Ketamine may also reduce opioid consumption and pain intensity throughout the postoperative period in this patient population. Furthermore, Loftus et al. (2010) reported that this benefit comes without an increase in side effects (24).
The danger associated to the consumption of ketamine was the focus of chapter 6. The cases of overdoses and deaths described in this chapter were excellent to confirm what the previous chapters had already stated: ketamine can be harmful, and even cause death, but when used in a medical setting, it is safe and effective. Recreational polydrug use seems to be much more of a problem.
There are several scientific reports about the deleterious effects of the chronic use of ketamine. For instance, Shanani et al. (2007) describe a series of nine patients, all of whom were daily ketamine users, who presented with severe dysuria, frequency, urgency, and haematuria. Urine culture, microscopy, cytology, computed tomography, cystoscopy, and bladder biopsies were performed to identify a relationship between recreational ketamine use and these symptoms. The urine cultures were sterile in all cases. Computed tomography revealed marked thickening of the bladder wall, a small capacity, and perivesicular stranding, consistent with severe inflammation. At cystoscopy, all patients had severe ulcerative cystitis. Cessation of ketamine use, with the addition of pentosan polysulfate, appeared to provide some symptomatic relief (25). Also, Tsai et al. (2009) outline the impact of ketamine abuse on the genitourinary tract in a study with eleven patients with urinary tract symptoms and a history of ketamine abuse in recent years. As the patients studied by Shanani et al. (2007), the most common complaints were dysuria, frequency, urgency, and haematuria. All biopsy specimens showed infiltrations of granulocytes (mostly eosinophils) and mast cells within the bladder tissue. Some of those patients developed irreversible histological changes in the urinary tract (26). Finally, Huang et al. (2011) specify the case of a nineteen-year-old woman
with a two-year history of inhaled ketamine abuse (6 g per day) presented with frequent (five to ten times per hour), urgent, and painful haematuria. She also had flank pain. Multiple petechial haemorrhages were seen in her bladder on cystoscopy. Biopsy of bladder mucosa revealed inflammatory infiltration with lymphocytes and eosinophils. Retrograde pyelography showed bilateral hydronephrosis and “walking-stick ureters”, as shown in figure 7.1, with partial bilateral obstruction (27).
Figure 7.1: Retrograde pyelography showing bilateral hydronephrosis and ureters with
segmental bending (arrows) and straightening of both ureters in a nineteen-year-old woman who used to inhale six grammes of ketamine per day (27).
In a medical setting, the 1992 version of the Physician’s Desk Reference already indicated that ketamine use is usually devoid of life-threatening side effects and that several instances of unintentional administration of overdoses of ketamine of up to ten times that usually required for surgical anaesthesia have been followed by
complete recovery (28), which is corroborated by the data retrieved in chapter 6. As Karl Jansen states in his book “Ketamine: dreams and realities”: “[…] regardless of a good safety record in medicine, the situation in a club or party is very different from lying in a hospital bed with physicians and nurses nearby. Private homes hold their own dangers in the form of bathrooms, pools, stairs, and burning cigarettes” (7).
Ketamine analogues, such as phencyclidine (PCP), can produce stronger euphoriant and psychedelic effects. PCP use spread in the 1970s. When PCP is snorted or smoked (for example, using dipped tobacco or cannabis cigarettes in the liquid form of PCP or sprinkled its powder form on a leafy material, like tobacco or cannabis), the effects are felt within five minutes and last up to six hours. PCP can also be injected, although this appears to be a less common route of administration. It became infamous for its recurrent binges, when users would take it repeatedly for consecutive days without eating or sleeping (8), a pattern of use also seen in crack cocaine users. By the mid-80s, PCP use began declining, perhaps partly as a result of the increased popularity of ketamine and crack cocaine. The fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) devoted a separated session to this substance entitled “Phencyclidine (or phencyclidine-like)-related disorders” in the chapter about substance-related disorders (29). The most recent version of the DSM (the DSM-5) places PCP into the “Hallucinogen-related disorders” category, with classical hallucinogens, in the substance-related disorders chapter (13).
Although there is a massive load of scientific data about ketamine, its short- and long-term effects on depression and chronic pain, as well as its side effects, need to be further studied with rigorous RCTs, with long follow-ups. This is urgent considering that the prescribed off-label use of ketamine is increasing. Moreover, additional research is required to determine optimal dosing schemes, route of administration, and treatment schedules.
It is time to set aside the old war on drugs narrative and embrace the use of ketamine for depression and chronic pain as there is evidence that it can have significant efficacy in treating these disorders. It seems probable that a balanced realistic approach towards ketamine use for depression and chronic pain will at least do no harm and may even have a more favourable outcome for public health than the negative approach from the war on drugs narrative. In a genuine risk versus benefit analysis, ketamine may pass the test.
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