Ketamine Pharmacology

Ketamine is a dissociative anesthetic that acts mainly via the N-methyl-D-aspartate (NMDA) receptor in the brain by inhibiting the reuptake of dopamine, norepinephrine, and serotonin, thus intensifying the effects of these neurotransmitters. ^{Reference Mion and Villevieille8} Ketamine can be administered via all routes and can be compounded into a flavored drink for oral administration to mask its bitter taste. ^{Reference McNulty and Hahn9}

Ketamine stability has been reported in some studies. Closset et al. was able to show that ketamine is stable in a Becton Dickinson^® (BD) syringe for up to 50 days. ^{Reference Closset, Hecq and Gonzalez10} Foy et al. was able to determine that ketamine was stable at 33°C for at least 7 days in the patient-controlled analgesia systems between preparation and administration. ^{Reference Foy, Poinsignon and Mercier11} Huvelle et al. reported that ketamine diluted in 3 mL propylene syringes may be chemically stable for up to 180 days at room temperature at 25°C, while Daouphars et al. demonstrated that ketamine is stable in a polyvinyl chloride bag for 7 days at 23ºC, though ketamine was mixed with oxycodone in the latter. ^{Reference Daouphars, Hervouet and Bohn12,Reference Huvelle, Godet and Hecq13}

Conclusively, ketamine is likely stable over a range of 25 to 33°C for about 7–180 days. This underscores the importance of ketamine in settings where logistics for refrigeration and limited storage, safety of supply routes, lack of timely resupply of medications, and inadequate facilities for cardiopulmonary monitoring post-use are a challenge. ^{Reference Beiler, Barraud, Vigneron and Demoré14}

Ketamine stimulates respiration and maintains airway patency during sedation and anesthesia over a wide range of doses due to its bronchodilator effects, thus contributing to its safety in acute pulmonary diseases such as asthma and acute exacerbation of COPD. ^{Reference Girish and Joshi1,Reference Eikermann, Grosse-Sundrup and Zaremba15} Ketamine also provides amnesia, analgesia, immobility, and loss of consciousness, and can result in centrally mediated dose-dependent fall in body temperature. ^{Reference Girish and Joshi1,Reference Ikeda, Kazama and Sessler16} Also, it affects core temperature by reducing the magnitude of redistribution hypothermia. ^{Reference Girish and Joshi1,Reference Ikeda, Kazama and Sessler16} Thus, there is often no need for extensive monitoring post-use. Additionally, ketamine is often used for co-induction with other anesthetics such as propofol, thus enhancing their synergistic action and provide cardiopulmonary stability, and can antagonize alfentanil-induced hypoventilation in healthy male volunteers. ^{Reference Girish and Joshi1,Reference Persson, Scheinin and Hellström17}

The enduring sedative, hypnotic, and psychodysleptic effects of ketamine increase the risk of its misuse. Serious adverse effects have been reported in long-term use of ketamine. Adverse effects involving various systems have been reported; however, central nervous system complications are most common. Encouragingly, most of these side effects tend to subside with abstinence because ketamine dependence is rare. ^{Reference Zanos, Moaddel and Morris18} Musculoskeletal effects such as myoclonus, twitching, spasms, ataxia, and fasciculation have been reported. ^{Reference Bokor and Anderson19}

Long-term ketamine use may affect the gastrointestinal system, which may result in epigastric pain, hepatic dysfunction, and impaired gallbladder activity. ^{Reference Bokor and Anderson19,Reference Liu, Ng and Tam20} Incidentally, patients inhaling ketamine may be more prone to epigastric pain, recurrent vomiting, and gastrointestinal bleeding, which often precedes genitourinary symptoms. ^{Reference Liu, Ng and Tam20} Genitourinary effects of chronic ketamine use such as lower urinary tract dysfunction and increased sexual impulses have been reported. ^{Reference Zanos, Moaddel and Morris18} Even though death from acute direct toxicity is rare, ketamine-induced uropathy (KIU) is the most dreaded of ketamine toxicity, and it is seen where ketamine is given as prolong infusion or in chronic abuse. ^{Reference Bokor and Anderson19,Reference Jhang, Hsu and Kuo21} KIU may present as hydronephrosis, ureteral stenosis, cystitis, vesicoureteral reflux, bladder fibrosis, severe pelvic pain, and storage symptoms as a result of a loss of bladder control. ^{Reference Girish and Joshi1,Reference Castellani, Pirola and Gubbiotti22–Reference Li, Wu and Cha24}

Role of Ketamine

Despite the reported misuse and adverse effects, ketamine is still an important drug in providing essential, non-essential, and specialist medical and surgical care. ^{Reference Nowacka and Borczyk25} Ketamine is useful for pain control, sedation, cheap and safe anesthesia in LMICs and in reactive airway diseases. Additionally, it may have a role in patients with sepsis as an immunomodulator and prevention of cancer growth, and it provides hemodynamic stability in hemodynamically unstable or critically ill patients. ^{Reference Girish and Joshi1,Reference Nowacka and Borczyk25–Reference Gao, Rejaei and Liu27} Besides, ketamine has been successfully used in sports or trauma medicine, after a sudden onset natural disaster mass casualty incident, crisis or conflict zones, and veterinary medicine as an analgesic or anesthetic. ^{Reference Girish and Joshi1,28,29} Ketamine has also been used to supplement the analgesic effect of local anesthetics. ^{Reference Swain, Nag, Sahu and Samaddar30,Reference Oham, Ekwere and Tobi31}

Ketamine and Resource-Poor Countries

The burden of disease preventable by surgery is on the increase worldwide, and about 95% of the estimated 4.8 billion people who lack access to safe, affordable surgical and anesthetic care reside in resource-poor countries where the poorest world’s population receives only 3.5% of surgical procedures. ^{Reference Alkire, Raykar and Shrime32} The risk of financial hardship from medical care is higher in these settings due to out-of-pocket health care spending. ^{Reference Lin, White and Glover33,Reference Shrime, Dare, Alkire and Meara34}

In a study by Lin et al., ^{Reference Lin, White and Glover33} cost (73%) and lack of providers (8.8%) were reported as the most common barriers to surgical care and outcomes. Regrettably, the physician-to-population densities range from 0 to 4.9 per 100 000 in most LMICs, which worsen the anesthesia workforce crisis. ^{Reference Hoyler, Finlayson and McClain35} The World Federation of Societies of Anaesthesiologists argued that a minimum of 10 anesthesiologists per 100 000 is required to provide safe anesthesia. ^{Reference Weiser, Bekele and Roy36} Moreover, many anesthesia providers in LMICs are either nurses or clinical assistants with limited formal advance anesthetic training. ^{Reference O’Riordan and Mannion7,Reference Vo, Cherian and Bianchi37,Reference Gajewski, Pittalis and Lavy38}

Ketamine use has contributed significantly to improved access to basic surgical and obstetric care in LMICs because its use doesn’t require sophisticated equipment for monitoring and expertise. In a survey done in 22 LMICs, availability of ketamine (71.5%) far exceeded the availability of reliable electricity (59%), running water (62.4%), and supplemental oxygen (45.2%). ^{Reference Vo, Cherian and Bianchi37}

The successful use of ketamine in LMICs was reported by Masaki et al.; the study typified the feasibility and safety of ketamine for essential surgeries where no anesthetic is available. ^{Reference Masaki, Makin and Suarez39} Similarly, Guha et al. reported how successful it was for non-anesthetists to provide procedural sedation in acutely painful conditions with minimal side effects and no mortality. ^{Reference Guha, Suarez and Omotayo40} However, these studies might have overstated the role of non-physician anesthetists in meeting surgical needs in low-resource settings without considering the burden of other surgical care needs where the use of ketamine might not be indicated.

Ketamine and Disaster

Disaster is defined as “a sudden event causing severe destruction of infrastructure, people and the economy and which overwhelms the resources of that country, region or community." ^{Reference Craven41} These sudden onset disasters may be caused by natural events such as earthquakes, tsunamis, and disease epidemics or man-made disasters such as war and industrial accidents, and often produce mass casualties and later evolve to create complex humanitarian emergencies. Disasters and armed conflicts pose logistical challenges for medical missions managing alternative care sites, hospitals, and clinics, because they are often characterized by high numbers of trauma cases. ^{Reference Craven41–Reference Wedmore and Butler43} These challenges are more in developing countries where the health care response is already impaired, thus complicating the response. ^{Reference Craven41–Reference Wedmore and Butler43} Additionally, the presence of other surgical conditions aside from trauma cases often compounds the surgical care needs, as these needs differ from context to context and depend on local means and capabilities. ^{Reference Trelles Centurion, Van Den Bergh and Gray42}

During these medical missions, absence of anesthesia machines and ventilators, inadequate supply of medical gases, electricity to power oxygen concentrators and medications, and poor state of Post Anaesthetic Care Units (PACU) are common ^{Reference Craven41} – hence the need for anesthesia techniques that will ensure maintenance of spontaneous respiration that is essential for rapid emergence after anesthesia with the opportunity to bypass the PACU. ^{Reference Craven41} These challenges make the anesthetist fall back on deep sedation with ketamine with or without regional anesthesia or benzodiazepines such as midazolam for managing the peculiar circumstances during these crises. ^{Reference Craven41,Reference Trelles Centurion, Van Den Bergh and Gray42,Reference Anagnostou, Michas and Giannou44} Ariyo et al. reported ketamine as essential for medical missions for anesthesia without tracheal intubation in a 6-year review of the humanitarian activities of Doctors Without Borders. ^{Reference Ariyo, Trelles and Helmand45} Also, the medical mission during the aftermath of the earthquake in Haiti performed 90% of their surgeries under ketamine anesthesia. ^{Reference Craven41,Reference Rice, Gwertzman, Finley and Morey46} In addition, medical missions often work alongside local nurse anesthetists and health technicians who have vast experience monitoring patients receiving ketamine anesthesia.

A 10-year review of ketamine administration in prehospital combat patients emphasized the relevance of ketamine in moderate to very severe combat injuries; however, only about 5% of the studied patients received ketamine. ^{Reference Torres, Bebarta and April47} Ketamine recipients experienced lower survival rates, perhaps due to the severity of their injuries when compared to non-recipients of ketamine. ^{Reference Torres, Bebarta and April47} The possibility of poor record keeping during combat may have affected the study outcome as well.

Challenges, such as distance from suppliers, security of supply routes, availability of cold chain conditions in areas where supply may be held for weeks and unpredictable resupply timing, make ketamine an essential drug that should be stocked in large quantities during disasters and armed conflicts. ^{Reference Craven41,Reference Rice, Gwertzman, Finley and Morey46} Also, the ability to provide general anesthesia in a spontaneously breathing patient makes ketamine invaluable in disaster and armed conflict zones, as it minimizes the need for sophisticated equipment other than a pulse oximeter and a sphygmomanometer. ^{Reference Dohlman2,Reference Trelles Centurion, Van Den Bergh and Gray42,Reference Ariyo, Trelles and Helmand45} In addition, ketamine is reported to be stable in varying concentrations and conditions. ^{Reference Daouphars, Hervouet and Bohn12,Reference Beiler, Barraud, Vigneron and Demoré14}

Ketamine and Pain Management

About 50% of the world’s poorest countries receive less than 1% of opioid distributed worldwide, where about 61 million people experience about 6 billion days of serious health-related suffering that could be alleviated with access to palliative care and pain relief. ^{Reference Bhadelia, De Lima and Arreola-Ornelas48} This gap can be bridged with ketamine as it is cheap, accessible, easy to administer, highly effective, less addictive (dependence), and can reduce opioid consumption. Low dose ketamine is useful in managing acute and chronic pain, according to existing guidelines. ^{Reference Nowacka and Borczyk25,Reference Ragazzoni, Kwizera and Caviglia49,Reference Pribish, Wood and Kalava50} Also, ketamine may have an important role to play as a part of the opioid-sparing multimodal pain care strategy that could be explored in controlling the opioid crises. ^{Reference Karlow, Schlaepfer and Stoll51}

In contrast, Ragazzoni et al. reported that low dose ketamine does not reduce the cost of postoperative pain management after surgery nor does it reduce morphine consumption when a ketamine group was compared with a control group. ^{Reference Ragazzoni, Kwizera and Caviglia49} Despite conducting the study in a resource-limited setting, the use of low dose ketamine and elderly study participants were concerns in the study. ^{Reference Ragazzoni, Kwizera and Caviglia49}

Nonetheless, the consensus is that a sub-anesthetic dose of ketamine has a role to play in the management of pain, especially when used in combination with opioids. ^{Reference Ragazzoni, Kwizera and Caviglia49,Reference Bansal, Miller, Ferguson and Burns52} Additionally, ketamine use has been successful in managing pain crises following sickle cell disease, a commonly seen condition in resource-poor settings due to the poor practice of premarital genetic counseling. ^{Reference Lubega, Desilva and Munube53}

Ketamine is a drug to consider for refractory or severe headache, despite the outcome of the THINK trial by Benish et al. ^{Reference Robblee and Grimsrud54,Reference Benish, Villalobos and Love55} In the study, intranasal ketamine was not superior to intravenous metoclopramide in managing refractory headache. ^{Reference Robblee and Grimsrud54,Reference Benish, Villalobos and Love55} The intranasal route of administration and small sample size were concerns in the study. ^{Reference Benish, Villalobos and Love55} Evidence of the efficacy of ketamine in the management of headache is limited and inconsistent; however, it is still considered a second-line choice where headache is associated with significant aura. ^{Reference Robblee and Grimsrud54}

Ketamine and Psychiatry

The role of ketamine in psychiatry has increased in recent years. ^{Reference Pribish, Wood and Kalava50,Reference Schoevers, Chaves and Balukova56,Reference Gautam, Mahajan and Sharma57} Ketamine has been used for treatment-resistant posttraumatic stress disorder (PTSD), substance use disorder, anxiety disorders, alcohol use disorder, refractory status epilepticus, and in treatment-resistant depression, especially with suicidal tendency. ^{Reference Gautam, Mahajan and Sharma57–Reference Dakwar, Levin and Hart62} Low dose ketamine has been reported to be highly beneficial in the management of major depression. ^{Reference Xu, Hackett and Carter63} Ketamine may be protective or preventive against the development of PTSD in war-wounded soldiers as reported by Mion et al. ^{Reference Mion, Le Masson, Granier and Hoffmann59} The early introduction of ketamine in refractory status epilepticus has been advocated and may be more effective when combined with either benzodiazepines, such as midazolam, or hypothermia. ^{Reference Yan, Peng, Jing and Wang64}

Ketamine and Sedation

Ketamine is useful for procedural sedation across many specialities. ^{Reference Guha, Suarez and Omotayo40,Reference Hayward, Regan, Glasheen and Burns65,Reference Abdollahpour, Saffarieh and Zoroufchi66} Despite the controversy surrounding the issue of raised intracranial pressure, current evidence has shown that ketamine may be neuroprotective when used for sedation and perioperative care of patients with acute traumatic brain injury, especially in the presence of inflammation, pain, and stress. ^{Reference Farrell and Bendo67–Reference Cheung and Yew69} However, limited evidence revealed increased risk of neurotoxicity in the developing brain, which may result in disturbances in brain development during perinatal and neonatal exposure. ^{Reference Cheung and Yew69} There may be a need to reassess the use of ketamine in pregnancy and early neonatal period.

Ketamine Misuse and Supply

Ketamine misuse affects all countries; however, it is most common in East and Southeast Asia, especially China, Hong Kong, and Taiwan. ^70–72 New psychoactive substances (NPS) including ketamine are mostly supplied from East and Southeast Asia, including India; however, supplies have been noted from Europe and other destinations. ^71,72 Ninety-six per cent of the ketamine reportedly seized worldwide between 2013 and 2017 was in Asia. ⁷⁰ Countries of the golden triangle are a major supply of illicit ketamine to China, accounting for the main source of the drug up till 2019. ⁷³ Epidemiology of ketamine abuse revealed it is common among club goers, and addicts are more likely to be younger and of female gender. ^70,73

In 2013, ketamine was reported as the second most abused drug among Chinese populations in a survey done by China’s National Narcotics Control Commission (NNCC). ^{Reference Ma and Chu74} Consequently, China and other East and Southeast Asian countries increased crackdown on the supply of NPS and other illicit drugs, thus resulting in a noticeable decline. ^71,73 Despite these efforts, trafficking of illegal ketamine continues to be a problem, and it is becoming difficult to retain the achievements, so far. ^71,73 Ketamine has been associated with the highest rate of price increase (2016–2018) when compared to other illicit drugs in China, perhaps due to a strong market demand and high profit margins following the increased crackdown. ⁷¹

However, the threat of ketamine abuse is still not widespread compared to cocaine, heroin, or methamphetamine. ⁷⁵ Although the misuse of NPS, including ketamine, may be as low as 0.03% in Africa, the increasing crackdown on cheap drugs, such as tramadol and codeine, in Africa, may result in drug gangs falling back on drugs, like ketamine, to stay in business. ^70,76

Consequences of Ketamine Ban

Under the international control system for the manufacture, distribution, transfer, and use of drugs, ketamine is listed as a Schedule III drug (Table 4) due to its potential to cause physical or psychological dependence while it is placed on the World Health Organization essential medicine list. ^{Reference Liao, Tang and Hao6,Reference Burke-Shyne, Csete and Wilson77,78} Scheduling ensures international obligations for states to implement regulatory processes that meet or exceed requirements established by the treaties that regulate these substances.

Table 4. Drug scheduling ^a

Notes:

^a Drugs or substances used to make drugs are classified into 5 distinct categories or schedules. Accessed from www.dea.gov/drug-information/drug-scheduling.

Once a drug is reclassified as a Schedule I drug, the impact could result in onerous regulations, limited financial resources, lack of training/awareness of professionals, fear of prosecution/sanctions following possession of the drug, fear of drug diversion, cultural attitudes toward the drug, problems in sourcing the drug, trade control measures, and fear of addiction among member nations. ^{Reference Vargas-Schaffer79} Prioritizing restrictive control to the detriment of ensuring adequate availability of and access to some of the controlled medicines may be perceived as a human right violation. ^{Reference Burke-Shyne, Csete and Wilson77} The burden of diseases preventable by surgery may worsen due to over-restricted controls.

Fifteen out of the 46 essential medicines of potential relevance to safe and quality perioperative care are currently scheduled under international drug control. ^{Reference Nickerson, Pettus and Wheeler80} Resultantly, high-quality anesthesia and analgesic medicines are often not available where needed. A closer review of the fight against cannabis and cocaine misuse has revealed that restrictive legislations tend to encourage the proliferation of adulterated drugs, amplify drug trafficking, medicrime, and drug misuse. ^{Reference Klein81,Reference Usman82}

The ketamine petition sent in 2015 as China’s fourth petition on ketamine since 2006 to lobby the United Nations to change the status quo regarding ketamine failed; this decision doesn’t mean China won’t continue to push, more so that China wields more international influence amidst competing political and economic interests in the global scene. ^{Reference Liao, Tang and Hao6,28} Although it is a common practice in international politics to trade off support for a certain policy for political capital on other policies that may seem like a right idea, it is reasonable that high income countries may tread softly if another ketamine petition emerges.