Therapeutic Uses of Cannabis

• Extracts of the cannabis plant (cannabinoids) are thought to act primarily on CB1 and CB2 receptors.¹
• CB1 receptors are found mainly in the central nervous system, but also in dorsal root ganglia, sympathetic ganglia, adrenal gland, heart, lung, reproductive tissues, urinary bladder, gastrointestinal tissues. They are found on pain pathways in the brain and spinal cord, as well as terminals of peripheral nervous system primary afferent neurons.
• CB2 receptors are principally located in immune cells.
• Cannabinoid receptors play an important role in a variety of physiological processes including metabolic regulation, craving, pain, anxiety, bone growth, and immune function.
• Naturally-occurring chemicals (endocannabinoids) have been identified which are thought to act as 'retrograde synaptic messengers', being released by post-synaptic neurones and travelling backwards to suppress pre-synaptic neurotransmitter release.
• Stimulation of this system will result in various therapeutic effects.
• The therapeutic use of cannabis has to date largely focussed on the control of pain and muscle spasm, and its beneficial potential in other areas has not as yet been fully explored.

Indications

• The Notice of Compliance with Conditions authorises the use of Sativex as an adjunct for the symptomatic relief of neuropathic pain of at least three months duration in adult patients with multiple sclerosis (MS).¹
• Other therapeutic uses of Sativex currently being explored include the relief of muscle spasm in MS,⁴ non-MS neuropathic pain,³ cancer pain ⁵ and MS bladder dysfunction.⁶ These are being addressed in the pre-marketing European trials.⁷
• Early trials are also underway which are looking at the use of Sativex in spinal cord injury,⁸ rheumatoid arthritis,⁹ and peripheral neuropathy secondary to diabetes and AIDS.³

Contraindications

• Known or allergy to cannabinoids or other constituents of Sativex (propylene glycol, ethanol or peppermint oil)³
• Patients with significant hepatic disease (due to the ethanol content), renal dysfunction (cannabinoids are excreted via the kidney)³
• Serious cardiovascular disease, e.g. IHD, significant arrhythmias, unstable hypertension, severe cardiac failure (sympathoexcitation, bradycardia and cardiovascular depression in animal experiments)¹⁰
• A history of schizophrenia or other psychotic disorder (formally cited by the manufacturers, but paradoxically the use of cannabinoids in the treatment of schizophrenia is being explored)
• History of substance abuse including alcohol abuse - Sativex has addictive potential and should be avoided³
• Reproductive issues:
  • Evidence that cannabinoids are associated with reproductive toxicity in early gestation¹¹
  • Women of reproductive age should use reliable contraception
  • Spermatogenesis can be affected¹²
  • Male patients should maintain reliable contraception for the duration of therapy and for three months after
• Lactation - degree with which cannabinoids are excreted in breast milk is unknown³
• Safety and efficacy of Sativex not yet been established in patients under the age of 18²

Warnings and Special Precautions

• Warn patients they may get 'intoxication-type reactions' - e.g. sudden changes in mood, decreased cognitive performance and memory, alteration in perception of reality and time, and lack of inhibition.¹³ These effects are dose-related.³
• Patients should be warned not to drive or do any activity which involves judgement or co-ordination whilst taking Sativex.
• Use with caution in patients with pre-existing heart disease, arrhythmias, cardiac failure, poorly controlled hypertension, bradycardia, tachycardia and postural hypotension.^9,14,15
• Epilepsy - there is evidence that seizure threshold is related to activity at CB1 and CB2 receptor sites.¹⁶
• There is limited data on use in the elderly, so patients should be carefully monitored.³

Dosage and Administration³

• Patients should start with one spray every four hours up to a maximum of four sprays a day, and then self-titrate according to response.
• Warn the patient that it can take a week or more to find the right dose and to watch for symptoms of intoxication.
• Pre-marketing trials found that the average dose used was five sprays a day. There is limited evidence with doses higher than twelve sprays daily, although some patients may require this.
• The patient should spray directly below the tongue or towards the inside of the cheek, varying the site at each dose. Avoid spraying on inflamed areas. The spray should never be aimed at the pharynx as this can cause irritation.

Adverse Effects

• The commonest adverse effects during pre-marketing trials were headache, impaired balance, depressed mood and irritation at the site of administration.
• Syncopal attacks relating to postural hypotension have been identified.
• One case of a causal relationship between Sativex and suicidal ideation could not be ruled out, but the incidence of depression was consistent with that observed in populations of multiple sclerosis patients followed for a prolonged period of time.
• Hallucinations, episodes of paranoia and other psychotic symptoms have also been reported.³

Monitoring³

No routine laboratory monitoring is required other than that necessary to monitor the patient's condition and any concomitant medication. The patient should however be assessed regularly to see whether continued administration of Sativex is appropriate, due to its addictive potential.³

Interactions

• Sativex can potentiate the action of opioids, particularly fentanyl and alfentanil, and amitriptyline.
• Cannabinoids are also known to have an affect on drugs which rely on protein-binding transport systems, such as verapamil, so post-marketing trials are likely to identify many more interactions in the future.^3,17

Prescribing an Unlicensed Drug^18,19

A drug which is not yet licensed for UK use can be prescribed on a named patient basis, but be aware of the following issues:

• The doctor who signs the prescription takes full responsibility for the outcome and cannot cite the pharmaceutical company as co-defendant in any civil legal action arising from a serious untoward event.
• Make sure that both you and the patient are fully conversant with the contra-indications, special precautions, and adverse reactions.
• Record the issues you discussed with the patient.
• Monitor the patient regularly.