Current Scheduling Status
None
Year(s) and type of review / ECDD meetings
Drug Class
Recommendation (from TRS)
Substance identification
Clonidine (INN, CAS 4205-90-7) exists in two tautomeric forms, 2-[(2,6-dichlorophenyl)iminoJimidazolidine and 2-(2,6-dichloroanilino)-2-imidazoline, and is also known as clonidin, clonidinum and Catapres. No stereoisomeric forms exist.
Similarity to known substances and effects on the CNS
Clonidine is a centrally active drug which appears to exert its actions at alpha adrenoceptors. Acting at these sites, it reduces blood pressure; decreases release of norepinephrine and typically produces sedation. In laboratory animals clonidine exhibits analgesic actions. It has some anxiolytic effects in humans, but is not a reliable anti-anxiety agent. While it does not act at morphine receptors, clonidine suppresses some of the signs and symptoms of the morphine withdrawal syndrome in physically dependent laboratory animals, in human subjects in controlled experiments and in clinical situations. In most respects.clonidine does not resemble any known ‘psychoactive substance scheduled under either international treaty.
In humans, about 40-50% .of the dose absorbed is excreted as unchanged clonidine. None of the drug’s several metabolites appear to be pharmacologically active. The duration of action of clonidine is 6-8 hours and it must be given several times daily to maintain its effects.
Dependence potential
Clonidine is self-administered at some doses by rats and monkeys. Its reinforcing effects do not appear to be strong and are not reliably found by all investigators. Self-administration is blocked by dopaminergic antagonists, but is not attenuated by naloxone. These findings suggest that catecholaminergic rather than opioid mechanisms are involved. In drug-discrimination studies where animals were trained to discriminate between morphine and saline, clonidine was generalized to saline. When clonidine was given repeatedly, tolerance developed to its sedative effects, and in some cases also to its analgesic effects. Primary physical dependence has not been demonstrated in animals. Clonidine does not produce
classical opioid effects nor does it substitute completely for morphine in morphine-withdrawn animals, but it does suppress in a doserelated manner some of the signs (e.g., hyperactive adrenergic effects) of morphine withdrawal induced by opioid antagonists or drug deprivation. Experiments on cross-tolerance between opioids and clonidine have given inconclusive results. Most human subjects given clonidine find that it produces a form of sedation that is not associated with euphoria. Subjects treated with clonidine usually stop taking it because they dislike the side effects. Even subjects undergoing methadone detoxification sometimes prefer placebo to clonidine. Nevertheless, tolerance and a form of physical dependence develop in humans when clonidine is given chronically. The withdrawal syndrome includes agitation, restlessness, insomnia, headache, palpitations, tachycardia, sweating, nausea, vomiting and abdominal pain. However, no drug-seeking behaviour is associated with these symptoms. Blood pressure begins to rise about 18 hours after administration of the drug is discontinued. A number of other antihypertensive agents also sometimes cause withdrawal symptoms.
Actual abuse and or/evidence of likelihood of abuse
There are no well documented reports of clonidine abuse, nor is there any evidence of recreational use, despite widespread availability in many countries where it is not subject to special
controls. (No. known social or public health problems are associated with its use.
Therapeutic usefulness
Clonidine is used, widely in the treatment of hypertension, and has been marketed in Europe since 1966 and in the USA since 1974. The drug is also available elsewhere and has been tried in the treatment or prevention of a number of other clinical conditions, for example in migraine prophylaxis. Clonidine is also used for symptomatic relief of opioid. withdrawal symptoms. More recently it has been tried in the treatment of alcohol and nicotine withdrawal syndromes.
Recommendation
On the basis of the available. data concerning its pharmacolo gical profile, dependence potential and actual abuse, the Committee rated the likelihood of abuse of clonidine as. very low. and the therapeutic usefulness as moderate to high. The public health and social problems associated with the substance are véry few, if any, and the Committee considered that they did not warrant placing it under international control. The Committee did not recommend scheduling of clonidine.
Clonidine (INN, CAS 4205-90-7) exists in two tautomeric forms, 2-[(2,6-dichlorophenyl)iminoJimidazolidine and 2-(2,6-dichloroanilino)-2-imidazoline, and is also known as clonidin, clonidinum and Catapres. No stereoisomeric forms exist.
Similarity to known substances and effects on the CNS
Clonidine is a centrally active drug which appears to exert its actions at alpha adrenoceptors. Acting at these sites, it reduces blood pressure; decreases release of norepinephrine and typically produces sedation. In laboratory animals clonidine exhibits analgesic actions. It has some anxiolytic effects in humans, but is not a reliable anti-anxiety agent. While it does not act at morphine receptors, clonidine suppresses some of the signs and symptoms of the morphine withdrawal syndrome in physically dependent laboratory animals, in human subjects in controlled experiments and in clinical situations. In most respects.clonidine does not resemble any known ‘psychoactive substance scheduled under either international treaty.
In humans, about 40-50% .of the dose absorbed is excreted as unchanged clonidine. None of the drug’s several metabolites appear to be pharmacologically active. The duration of action of clonidine is 6-8 hours and it must be given several times daily to maintain its effects.
Dependence potential
Clonidine is self-administered at some doses by rats and monkeys. Its reinforcing effects do not appear to be strong and are not reliably found by all investigators. Self-administration is blocked by dopaminergic antagonists, but is not attenuated by naloxone. These findings suggest that catecholaminergic rather than opioid mechanisms are involved. In drug-discrimination studies where animals were trained to discriminate between morphine and saline, clonidine was generalized to saline. When clonidine was given repeatedly, tolerance developed to its sedative effects, and in some cases also to its analgesic effects. Primary physical dependence has not been demonstrated in animals. Clonidine does not produce
classical opioid effects nor does it substitute completely for morphine in morphine-withdrawn animals, but it does suppress in a doserelated manner some of the signs (e.g., hyperactive adrenergic effects) of morphine withdrawal induced by opioid antagonists or drug deprivation. Experiments on cross-tolerance between opioids and clonidine have given inconclusive results. Most human subjects given clonidine find that it produces a form of sedation that is not associated with euphoria. Subjects treated with clonidine usually stop taking it because they dislike the side effects. Even subjects undergoing methadone detoxification sometimes prefer placebo to clonidine. Nevertheless, tolerance and a form of physical dependence develop in humans when clonidine is given chronically. The withdrawal syndrome includes agitation, restlessness, insomnia, headache, palpitations, tachycardia, sweating, nausea, vomiting and abdominal pain. However, no drug-seeking behaviour is associated with these symptoms. Blood pressure begins to rise about 18 hours after administration of the drug is discontinued. A number of other antihypertensive agents also sometimes cause withdrawal symptoms.
Actual abuse and or/evidence of likelihood of abuse
There are no well documented reports of clonidine abuse, nor is there any evidence of recreational use, despite widespread availability in many countries where it is not subject to special
controls. (No. known social or public health problems are associated with its use.
Therapeutic usefulness
Clonidine is used, widely in the treatment of hypertension, and has been marketed in Europe since 1966 and in the USA since 1974. The drug is also available elsewhere and has been tried in the treatment or prevention of a number of other clinical conditions, for example in migraine prophylaxis. Clonidine is also used for symptomatic relief of opioid. withdrawal symptoms. More recently it has been tried in the treatment of alcohol and nicotine withdrawal syndromes.
Recommendation
On the basis of the available. data concerning its pharmacolo gical profile, dependence potential and actual abuse, the Committee rated the likelihood of abuse of clonidine as. very low. and the therapeutic usefulness as moderate to high. The public health and social problems associated with the substance are véry few, if any, and the Committee considered that they did not warrant placing it under international control. The Committee did not recommend scheduling of clonidine.
ECDD Recommendation
Scheduling/control not currently recommended
Link to full TRS
who_trs_775.pdf1.98 MB