Expert Committee on Drug Dependence Thirty sixth Meeting Geneva, 16 20 June 2014 1. Comments based on the review report a. Evidence on dependence and abuse potential Dependence has been demonstrated for ketamine in animal models. A limited number of cases of dependence in humans over the past 20 years have been described, but the terms are not consistently defined so it cannot be concluded that they are in fact dependence cases. Psychological factors that increase the probability of harm include, mood and anxiety conditions leading to self medication, and sensation seeking. Amongst these is a characteristic of the ketamine experience, which may be described as escape from reality. Some effects of ketamine may be due to an enhancement of dopamine activity, which may be of relevance for its euphoric, dependence producing, and psychotomimetic properties and it will appeal to substance users looking for extremes. It appears that the dissociative experience discourages some experimental users. Another reason for limited use mentioned in this study was the scarcity of the substance. No systematic studies on personality traits or other psychological factors leading to ketamine use or affecting the probability of harm were found. The most popular route of administration, when ketamine is used recreationally or experimentally, is the intranasal route, i.e. snorting the powder, or a solution from a vaporiser. Some long term users may use the intramuscular, subcutaneous or intravenous route as well. In the rave scene, oral administration by way of ketaminecontaining tablets occurs as well. The substance is difficult to synthesize and preparations are mainly used in hospitals and veterinary clinics, so illegal production is unlikely and diversion does not take place on a large scale. b. Risks to individual and society because of misuse Individual Ketamine can produce a depression of the central nervous system, resulting in hallucinations, disturbances in thinking, perceptions and in motor function. Rare cases of side effects like hypertension and lung edema have been reported in individuals who combined ketamine with other substances. Repeated use produces chronic impairments to episodic memory, which are reversible upon reduction of use. After prolonged and repeated infusion of ketamine infusions, liver injury may occur (100 hour continuous 36 th ECDD (2014), page 1
intravenous infusions). Standard psychometric tests did not reveal personality changes. Studies in healthy volunteers given ketamine have shown that ketamine produces a clinical syndrome with aspects that resemble key symptoms of schizophrenia, which may be experienced by the experimental or recreational substance user as an altered, psychedelic, state of mind. Substance users will not take ketamine in combination with protective agents like benzodiazepines. Moreover, compounds increasing the neurotoxic potency of ketamine might be co administered. Recreational use implies repeated exposure, whereas clinical use is mostly incidental. Long term adverse effects in long term users of ketamine have been reported, however are scarce. These included persisting impairment of attention and recall and a subtle visual anomaly (Jansen, 1990). In dependent users, use of the substance continues despite increasing apparent effects on their work or on their health. Society Information on ketamine is not routinely collected in population surveys and morbidity and mortality data collections. Public health problems have not been published during the past ten years. Levels of use in the general population, however, appear to be very low with higher levels in groups with access to the substance, such as medical and veterinarian professionals, and party drug users. Data from different studies in the USA and UK indicate that deaths due to ketamine abuse were in most cases due to acute multidrug intoxications. The WHO Uppsala Monitoring Centre (UMC) reported, out of 1277 reports from adverse effects from world wide PMS data, over a 2 year period, 25 cases of death, (2.0 %) and 1 case of sudden death (0.08%). In the EMCDDA report, a short overview of 13 reported deaths in which ketamine was involved were included. Only in 3 out of 13 fatal intoxications was ketamine solely identified (administered by injection). Two reports describe mixed drug fatalities. In the other cases, ketamine had either a minor role or there was a lack of data for proper evaluation. The conclusion of several authors cited in the critical review is that ketamine does not appear to currently pose a significant public health risk. c. Magnitude of the problem in countries (misuse, illicit production, smuggling etc) Ketamine has been misused as a hallucinogen for almost 30 years. Ketamine misuse is reported from a number of countries in Asia, Europe and North America. Misuse by medical personnel has also been reported. 36 th ECDD (2014), page 2
Due to the difficult synthesis of ketamine only diversion from legal sources has been observed. Levels of use in the general population appear to be very low with higher levels in groups with access to the substance, such as medical and veterinarian professionals, and party drug users.. The critical review includes cases of robberies in Mexico and France and attempted robbery of ketamine on its way from India to Kenya. Ketamine is illicitly manufactured in China, although India is also an important source of ketamine seized in the region. It is difficult to give an indication of the amount of the clandestine ketamine labs that are dismantled because often more than one illicit drug is manufactured. And not always is specified which lab makes what product. The INCB report (2012) mentions that 99% of all ketamine seizures worldwide in 2009 took place in Asia. Countries that reported seized material are China (including Hong Kong and Macao both SAR of China), Taiwan, India, Indonesia, Australia, Canada and El Salvador. Hydroxylamine hydrochloride, a precursor used in the manufacture of ketamine has been placed under national control in China in 2009. In the period 2003 2012, a number of clandestine ketamine laboratories were seized in Indonesia and the Philippines. Of the 72 countries responding to the WHO Questionnaire for the ECDD, 67 reported on the use of ketamine (mostly in Asia). Sixty two stated that Ketamine was currently authorized as a medical product in their country. Twenty eight respondents confirmed that ketamine was used in a harmful way and 12 reported on the extent of the harmful use. Fifty five reported that ketamine was controlled under legislation that was intended to regulate its availability. The ketamine critical review report prepared for the WHO ECDD in 2012, includes a survey on the use of ketamine among several hospitals in 4 countries in Africa (Ethiopia, Nigeria, Tanzania and Benin). Use of ketamine in anesthesia ranged between 15 to 49% of all the procedures in the surveyed hospitals. None of the hospitals reported cases of abuse or misuse. d. Need of the substance for medical (including veterinary) practice Ketamine is listed as an anesthetic both in EML 18th ed (2013) and in EMLc 4th ed (2013) and is authorized as a medicine in at least in 60 countries. Benzodiazepines are usually co administered with ketamine to reduce the occurrence of ketamine induced neurotoxicity. Ketamine hydrochloride is used as an analgesic and anaesthetic in human and veterinary medicine. Is one of the most commonly used anaesthetic agents in the developing countries (readily available, easy to use and inexpensive). In the critical review report for the 35 th ECDD, several Member States indicated that ketamine is indispensable for its indications in veterinary medicine. 36 th ECDD (2014), page 3
Other uses: Supplement to other anesthetics In obstetrics Adjuvant therapy of status asthmatics Immobilization Sedation Persistent hiccup Priapism Resistant bronchospasm e. Need of the substance for other purposes (e.g. industrial) No other uses and not applicable in industrial use. f. Measures taken by countries to curb misuse In 2006, the Commission on Narcotic Drugs (CND), in its resolution 49/6, and in 2007, in its resolution 50/3, called upon Member States to pay attention to the misuse of and trafficking in ketamine, in particular in East, South East Asia and South America, and to consider adopting a system of precautionary measures for use by their government agencies to facilitate the timely detection of the diversion of ketamine and controlling its use by placing ketamine on the list of substances controlled under their national legislation, where the domestic situation so requires. In its Annual Report for 2007, the International Narcotics Control Board (INCB) called on all Governments to implement Commission resolution 50/3 without delay. In its reports for 2008 and 2009 it called for the implementation of both resolutions 49/6 and 50/3. In 2008, in addition, the Board ʺdecided to request all Governments to provide it with information on the specific legal or administrative measures adopted pursuant to Commission resolution 49/6, including information on measures to control ketamineʺ. As of 1 December 2013, a total of 105 countries and territories have responded to the INCB. Of these, 63 countries and territories have already introduced an import authorization requirement for ketamine, and 57 countries and territories have introduced an export authorization requirement. 42 countries and territories do not require an import authorization and 48 do not require an export authorization. In 2009, a total of 55 Governments reported that ketamine had already been placed on the list of substances controlled under national legislation intended to regulate its availability. g. Impact if this substance is scheduled Ketamine is a widely used anesthetic and analgesic, especially in developing countries because it is easy to use and has a wide margin of safety when compared with other anesthetic agents. Fifty respondents reported that if ketamine was placed under 36 th ECDD (2014), page 4
international control, they would have the laboratory capacity to identify the substance. Six respondents indicated that the availability of ketamine for medical use will be affected if placed under international control. Data from the INCB and other UN bodies indicate that the vast majority of patients do not have access to controlled medications. There are many reasons for this, one of which is unduly restrictive laws and regulations in the countries. If ketamine is placed under international control, it can be assumed that its availability and accessibility will fall into the same level of other controlled medications, which would result a public health crisis. 2. Additional information to the critical review report Ketamine is also being used as an adjuvant analgesic and as an alternative analgesic in patients in palliative care. Studies indicate that Ketamine may reduce pain intensity in patients with advanced cancer and mixed pain syndromes (Mercadante, 2000; NHS, 2010). Neuropathic pain poorly responsive to titrated opioids and oral adjuvant analgesics (eg. antidepressant and/or anticonvulsant) particularly when there is abnormal pain sensitivity allodynia, hyperalgesia or hyperpathia. Complex ischaemic limb pain or phantom limb pain. Poorly controlled incident bone pain (often has a neuropathic element). Complex visceral / abdominal neuropathic pain. References: INCB. Report of the International Narcotics Control Board for 2012; Vienna: INCB, 2014 Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: A randomized, double blind, crossover, double dose study. J Pain Symptom Manage 2000;20:246 252. NHS Lothian. Ketamine Palliative Care Guidelines. Available in http://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0cd4 QFjAA&url=http%3A%2F%2Fwww.palliativecareguidelines.scot.nhs.uk%2Fdocume nts%2fketaminefinal.pdf&ei=z4r0u5a7hyj_oekogdgg&usg=afqjcnfsrnmhbg mns6ytvgjt0hy0hrgy1a&bvm=bv.66699033,d.zwu Accessed May 15, 2014. The critical review prepared in 2012 http://www.who.int/medicines/areas/quality_safety/4.2ketamine_criticalreview.pdf? ua=1 3. Other comments or opinions Ketamine has several important medical uses and when used appropriately, it is safe, effective and affordable. Millions of patients (humans and animals) currently benefit from the legitimate use of ketamine. 36 th ECDD (2014), page 5
4. Expert reviewer s view on scheduling with rationale In September 2002 the WHO ECDD had a pre review on ketamine. A critical review was performed in 2006. The WHO ECDD concluded that there was no significant public health issues posed by ketamine and that international control was unnecessary. It was suggested that the drug be kept under surveillance. During its 35th meeting, the WHO Expert Committee on Drug Dependence discussed the critical review report on ketamine and concluded that this information was not sufficient to warrant scheduling. Ketamine is widely used as an anesthetic in countries with limited resources and in many is the only option to provide anesthesia in less complex and in rural health care settings. Placing ketamine under international control would negatively impact its availability and accessibility for legitimate medical and veterinary practice and create a public health crisis. Many of the countries facing problem due to abuse or illicit trade, manufacture or diversion of ketamine have already taken control measures based on the suggestion by the INCB. Other countries may review their situation and if necessary establish national control measures based on reports of abuse/diversion/illicit trafficking and need for therapeutic use rather than placing ketamine under international control. The suggestion is to keep the medicine under surveillance to detect trends and is consistent with the recommendation made by the WHO 35 th ECDD. 36 th ECDD (2014), page 6