Cannabinoids

By | May 14, 2012

The cannabinoids are derived from the resin of the plant Cannabis sativa. The only known active constituent is 9-tetrahydrocannabinol (59-THC). Other cannabinoids are an oral synthetic nitrogen analogue of THC and intramuscular levonantradol. There are claims for their use in nausea and vomiting, appetite stimulation in HIV-infected patients, movement disorders and glaucoma. There have also been claims that cannabinoids are useful in the treatment of migraine and painful spasticity in multiple sclerosis and spinal cord injury. There is some evidence that they are analgesic in humans. A systematic review of nine randomized controlled trials has concluded that there need to be further trials into their use in spasticity and neuropathic pain but they have no place in the management of post-operative pain. A double-blind comparison with placebo in a patient with prior history of cannabinoid use has demonstrated an opioid-sparing effect in chronic pain.

Mechanisms of action

It is suggested from animal studies that cannabinoids reduce the behaviour believed to equate with the clinical syndromes of allodynia and hyperalgesia. From animal evidence, here summarized, it is believed that the brain is probably the site of action, but there is evidence for a spinal cord site of action.

1. Opioid receptor agonism. Perinatal exposure to cannabinoids results in analgesia, morphine tolerance and an abstinence syndrome when given naloxone. Naloxone and other opioid receptor antagonists, specifically the k1 antagonists block the antinociceptive actions of cannabinoids. They do not prevent the behavioural effects. An effect has been observed when the opioid receptor is blocked by spinal administration.

2. Cannabinoid receptor agonism. Cannabinoid receptors have been identified; CB1 receptors on central and peripheral neurons and CB2 receptors on immune cells. The identification and cloning of specific cannabinoid receptors has been followed by the identification of an endogenous ligand called anandamide. The function of these receptors and ligands remains unclear. Cannabinoid receptor activation reduces the amplitude of voltage-gated Ca2+ currents, thereby decreasing excitability and neurotransmitter release. The finding of further subclasses of receptors offers potential for separating analgesic actions from the harmful psychotropic actions by the development of synthetic analogues. The spleen contains cannabinoid receptors.

3. Prostaglandin metabolism. Anandamide is an intermediate product of arachidonic acid metabolism. Synthetic cannabinoids have been shown to reduce arachidonic acid-induced inflammation, presumably by an action on inhibition of eicosanoid synthesis.

Pharmacokinetics of Cannabinoids

59-THC is highly lipid-soluble and readily absorbed from the gastrointestinal tract and lungs. Bioavailability after oral ingestion is about 6%. It has, like other lipid-soluble compounds, a large volume of distribution. It is metabolized to polar water-soluble compounds before excretion by the kidney, although intestinal elimination accounts for some of the drug.

Clinical effects of Cannabinoids

The best that can be achieved with cannabis is an antinociceptive effect equivalent to 60 mg codeine. The anti-inflammatory effect is unlikely to be as valuable as the currently available drugs. There is inadequate evidence to support their use in the management of more complex pain. In addition to the actions described above, cannabinoids lower intraocular pressure. Inhalation of the drug is associated with carboxyhaemoglobin production, and intrauterine growth retardation and an increase in childhood leukaemia are features of the children of women who use cannabinoids in pregnancy. Central nervous system side-effects include psychomotor and cognitive impairment. Psychiatric syndromes encountered with cannabinoid use include mania, anxiety and depression, and there is a six-fold greater incidence of schizophrenia in heavy users than in non-users.

Any potential clinical benefit in the management of chronic pain must be weighed against the hazards of the drug, and the potential harm that may result from wide-spread availability and social acceptability if legalization were undertaken.

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