Cannabis-based medicinal products

Why the committee made the recommendations

Intractable nausea or vomiting can be defined as persistent nausea or vomiting that does not respond fully to optimised conventional antiemetics. Although there are different causes of intractable or persistent nausea and vomiting, evidence was only identified for the use of delta-9-tetrahydrocannabinol (THC), nabilone and dronabinol in people with chemotherapy-induced and radiotherapy-induced nausea and vomiting.

Limited evidence showed that nabilone, which is licensed in the UK for adults, resulted in complete or partial reduction in chemotherapy-induced nausea and vomiting. However, most of the studies were old, of low quality and used outdated antiemetic regimens that do not reflect current practice. Nabilone was also associated with more adverse events (drowsiness, dizziness and dry mouth), particularly in children. The committee noted that although use of cannabis-based medicinal products for intractable chemotherapy-induced nausea and vomiting would be short term, there was a lack of evidence on longer term adverse events, such as dependence and the development of psychological disorders. They identified this as a concern, particularly when considering repeated use. The committee also noted the limited evidence for children and young people. Based on these findings they were unable to make recommendations specifically for this group.

The committee agreed that nabilone may play a role in treating intractable chemotherapy-induced nausea and vomiting in people who have not had a full response to optimised conventional antiemetics. Based on the limited evidence, the committee only recommended that nabilone could be considered as an add-on treatment in adults with intractable chemotherapy-induced nausea and vomiting which persists despite the use of optimised conventional antiemetics.

The committee were aware that people may be taking other medication when using nabilone and were concerned about potential adverse drug interactions. They recommended that adverse drug interactions should be carefully considered when prescribing nabilone. The committee highlighted concerns for the use of nabilone with central nervous system depressants and other centrally active drugs. They recommended that healthcare professionals should think about these when considering nabilone and refer to the summary of product characteristics for further information on dosing, patient monitoring, contraindications and adverse events.

Evidence for the use of other cannabis-based medicinal products was limited and the committee were unable to make any practice recommendations. However, they made a recommendation for research to inform future guidance.

Nabilone is not currently licensed in the UK for children and young people under 18 years because its safety and efficacy has not been established. Therefore, the committee made another recommendation for research on the effectiveness of cannabis-based medicinal products in babies, children and young people with intractable nausea and vomiting.

Only 1 study was identified which included people with radiotherapy-induced nausea and vomiting. The committee noted that there are other causes of intractable nausea and vomiting but were unable to make further recommendations due to lack of evidence. Therefore, the committee made an additional recommendation for research.

How the recommendations might affect practice

The committee highlighted that the use of nabilone is uncommon in current practice and it is not used as first-line treatment for chemotherapy-induced nausea and vomiting. The recommendations could result in an increase in use of nabilone as an add-on treatment for adults with chemotherapy-induced nausea and vomiting, but the current level of use is uncertain.

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Why the committee made the recommendations

Some evidence showed that CBD reduced chronic pain, but the treatment effect was modest (an average improvement of about 0.4 on a scale ranging from 0 to 10). The evidence did not show a reduction in opioid use in people prescribed medicinal cannabis. Because the number of people who might benefit is large and the cost potentially high, an economic model was developed to compare benefits with the potential costs. The model used data from the trials in the base-case analysis but also assumed a larger potential benefit from cannabis-based medicinal products in various sensitivity analyses. In all cases, the potential benefits offered were small compared with the high and ongoing costs, and the products were not an effective use of NHS resources. The evidence included CBD in combination with THC, THC alone, dronabinol and nabilone so the committee named these products in the recommendation. The committee also agreed that the recommendation should follow the evidence and specify adults.

There was no evidence for the use of CBD alone (either as a pure product or containing traces of THC). Therefore, the committee recommended that CBD should not be offered unless as part of a clinical trial. People who have fibromyalgia or persistent treatment-resistant neuropathic pain are often taking high doses of medicines for pain relief over long periods. These can cause nausea, drowsiness, mood disturbance and fatigue. The committee noted that this is a significant population of people with chronic pain (around 15%). They therefore made a recommendation for research for CBD in adults with fibromyalgia or treatment-resistant neuropathic pain.

There was no evidence for intractable cancer-related pain or pain associated with painful childhood diseases. The committee agreed that cannabis-based medicinal products could potentially offer additional benefits for this group, for example, by allowing them to receive their care in an outpatient rather than an inpatient setting or by reducing the overall opioid use. They agreed to make a recommendation for research to explore the clinical and cost effectiveness.

How the recommendations might affect practice

Prescriptions of cannabis-based medicinal products for chronic pain are currently rare. GPs refer people with chronic pain to specialist pain services where clinicians on the Specialist Register with expertise in this area decide whether cannabis-based medicinal products should be prescribed. The new recommendation might reduce the number of these prescriptions.

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Why the committee made the recommendations

The committee agreed that the evidence showed benefits of THC:CBD spray (licensed product in UK: Sativex) for treating spasticity in people with multiple sclerosis. There were reductions in some measures of patient-reported spasticity and no difference in adverse events in the treatment or placebo groups, although much of the evidence was assessed as low quality. The committee agreed that the longer-term benefits of THC:CBD spray are likely to outweigh any potential harms, although it was not clear how benefits related to improvements in quality of life.

The committee considered the evidence from 2 published economic evaluations but noted that they had contradictory conclusions about the cost effectiveness of THC:CBD spray and were subject to potentially serious limitations. So they considered results from a new economic model developed specifically for the cannabis guideline. The model included data from all relevant trials, longer-term registry data and data on adverse events. In reflection of the trial evidence, the model predicted that the average person would receive a quality of life (QALY) gain equivalent to around 30 days perfect health with THC:CBD spray added to standard care. The acquisition costs of the treatment are offset by predicted savings in management costs. The model estimates that THC:CBD spray would offer sufficient QALY gains if reduction in spasticity led to a halving of management costs and the acquisition cost of THC:CBD spray was also reduced (in addition to the existing pay-for-responders scheme). The committee agreed that under these conditions THC:CBD spray could be recommended to treat moderate to severe spasticity in adults with multiple sclerosis if other pharmacological treatments had not been effective.

The committee agreed that the evidence for the effectiveness and safety of other cannabis-based medicinal products was much more limited. There is also currently no evidence on the cost effectiveness of products other than THC:CBD spray and in other clinical indications (for example, motor neurone disease and spinal cord injury).

The committee acknowledged that women are more likely to receive a diagnosis of multiple sclerosis than men. However, they considered this would not cause an inequality in relation to treatment.

Because there is limited evidence from trials on how reductions in spasticity affect quality of life and no evidence was found for conditions such as cerebral palsy, the committee agreed to make a recommendation for research to inform future guidance.

How the recommendations might affect practice

These recommendations are a change to NICE's previous guidance on treating spasticity in adults with multiple sclerosis, which did not support the use of THC:CBD spray. They are therefore expected to lead to THC:CBD spray being used as an add-on treatment for adults with treatment-resistant spasticity due to multiple sclerosis, with concomitant reductions in the need for supportive care.

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Why the committee made the recommendations for research

The only cannabis-based medicinal product available for the treatment of epilepsy is epidyolex, which is licensed specifically for Dravet and Lennox-Gastaut syndromes. All other cannabis-based medicinal products are unlicensed for epilepsy. The committee were aware from cases highlighted by stakeholders that individual patients have reported having fewer seizures with these medicines when other treatments have not fully controlled the seizures. But current research is limited and of low quality, making it difficult to assess just how effective these medicines are for people with epilepsy. Published randomised controlled trials have focused on the use of pure CBD in people with Dravet and Lennox-Gastaut syndromes. People with these epilepsy syndromes also report a very high rate of adverse events. Open-label studies (clinical trials in which the treatment and placebo groups are not disguised) of cannabis-based medicinal products in other types of epilepsy have also shown a very high level of adverse events (in up to 98% of people), but it was not possible to determine how many of these were due to the cannabis-based products.

The committee discussed the limited evidence and agreed that it did not warrant a practice recommendation. However, they also agreed that they should not make a recommendation against the use of cannabis-based medicinal products as this would restrict further research in this area and would prevent people who are currently apparently benefiting from continuing with their treatment. Specialists, people with epilepsy and their carers should continue to make treatment decisions in the best interests of each person with epilepsy, in line with the GMC's guidance for doctors. However, people seeking treatment for severe epilepsy should be made aware that currently there is no clear evidence of the safety and effectiveness of cannabis-based medicinal products.

The committee agreed that more evidence is needed on the effectiveness of cannabis-based medicinal products in severe treatment-resistant epilepsy and made a recommendation for research to inform future practice. They discussed that some individual funding requests are denied because of lack of evidence of effectiveness. More research across different types of epilepsy may address this evidence gap.

The committee discussed the constituents of cannabis-based medicinal products. They were aware that it is difficult to extract pure CBD without other cannabinoids being present in trace amounts and this varies depending on extraction methods. Some medicines contain either purified 'pure' CBD alone (with trace amounts of other cannabinoids) or CBD combined with higher than trace amounts of THC. Most studies of cannabis-based medicinal products for severe epilepsy have evaluated 'pure' CBD, but the committee agreed it is important to know whether adding medicinal amounts of THC to CBD offers benefits or affects the type of adverse events observed. They decided to make a recommendation for research on how the constituents of a cannabis-based medicinal product influence its effectiveness.

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Why the committee made the recommendations

Based on current legislation, the complexity of the conditions, and the licensed (nabilone and Sativex) and unlicensed status of these medicines, the committee agreed that the initial prescription of unlicensed cannabis-based medicinal products must be made by a specialist medical practitioner (a doctor included in the register of specialist medical practitioners [the Specialist Register]). They should also have a special interest in the condition being treated. The committee also agreed that THC:CBD spray should be initiated by a physician with special expertise in treating spasticity due to multiple sclerosis. Although there are no legal requirements for nabilone to be prescribed by a specialist prescriber.

There was limited evidence on who should prescribe and monitor cannabis-based medicinal products. Studies were conducted in Australia and Canada, and 1 study included participants from 8 different European countries. These countries have different healthcare systems, funding streams and legislation, which raised questions about their applicability to the prescribing of cannabis-based medicinal products in England. It was also not clear whether all products could be considered cannabis-based products for medicinal use as defined in the 2018 Regulations.

Guidance from the British Paediatric Neurology Association, based on current UK legislation and policy, advises that for children with intractable epilepsy, cannabis-based products should only be prescribed by a consultant paediatric neurologist. The committee agreed that for children and young people the initiating specialist prescriber for cannabis-based medicinal products should be a tertiary paediatric specialist with a special interest in the condition being treated (for example, for a child or young person with epilepsy, this would be a tertiary paediatric epilepsy specialist).

The committee noted that NICE's guideline on controlled drugs recommends that no more than a 30-day supply of a controlled drug is prescribed at any one time. Once their condition is stable, people taking cannabis-based medicinal products are likely to need repeat prescriptions. They will also need close monitoring of effectiveness and adverse effects, and dose adjustments. The committee agreed that there are potential burdens for patients associated with limiting prescribing and monitoring to tertiary care. They were aware of electronic prescription systems that could help patients to access prescriptions locally, but knew that these services vary by location. The committee discussed whether shared care would be appropriate and in the patient's best interest. They agreed that a shared care agreement could be considered, which could involve other healthcare professionals such as GPs and non-medical prescribers if they were confident to take on the responsibility of prescribing. The committee endorsed and agreed to reference NHS England's guidance on responsibility for prescribing between primary and secondary/tertiary care.

The committee agreed that after the initial assessment and prescription by a specialist, allowing other prescribers to prescribe cannabis-based products under specialist direction would improve access for patients.

The specialist initiating treatment should also be involved in monitoring, evaluation and dose adjustment. This should be part of a shared care plan with a clear division of responsibilities between the initiating specialist prescriber and the prescriber acting under their direction.

The committee noted that a shared care agreement should detail the responsibilities of all parties, including the patient and their family and/or carers. The committee highlighted that the agreement should include details of how communication between parties would be managed, how funding would be obtained and the frequency and nature of monitoring.

Because some patients may need long-term treatment, the agreement should ensure continuity of care by setting out what should happen when the patient, other prescriber or specialist moves location. This should include handover of responsibilities to other specialists or prescribers.

How the recommendations might affect practice

Currently, prescribing and monitoring cannabis-based medicinal products takes place in tertiary care. The recommendations focus on shared care after the initial prescription with the involvement of other healthcare professionals such as non-medical prescribers and GPs. This will allow a more holistic approach to care. Moving away from tertiary care may be cost saving for the NHS.

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Why the committee made the recommendations

The committee agreed a number of factors that should be considered before prescribing cannabis-based medicinal products, based on study data, summaries of product characteristics and committee experience. They highlighted these in a recommendation along with some of the contraindications from the studies of the effectiveness and safety of cannabis-based medicinal products for nausea and vomiting, chronic pain, epilepsy and spasticity.

The committee also discussed whether there were any particular considerations when prescribing cannabis-based medicinal products for babies, children and young people. They discussed the limited evidence about the effects in this group and were mindful about the potential effects on cognitive function. The committee agreed that when considering the balance of benefits and harms, it would be prudent to take into account the potential impact of treatment on brain and cognitive development, and the effect of sedation.

The committee discussed the importance of collecting data on the treatment, clinical outcomes and adverse events experienced by people prescribed cannabis-based medicinal products, to inform future guidance and use. They noted the ambition to develop a UK register outlined in NHS England and NHS Improvement's barriers to accessing cannabis-based products for medicinal use on NHS prescription, and supported this.

Many people use non-prescribed, over-the-counter or over-the-internet, cannabis-based food supplements. The committee agreed that when someone is prescribed cannabis-based medicinal products they should be advised to stop using any non-prescribed cannabis products. This will reduce the risk of any drug interactions and reduce the potential for people taking a higher dose of cannabis than prescribed.

How the recommendations might affect practice

These recommendations will help to guide prescribers on some of the important issues to consider when prescribing cannabis-based medicinal products. This may result in more prescriptions for cannabis-based medicinal products, which may increase costs to the NHS. However, if symptoms are reduced with the use of cannabis-based medicinal products this may ultimately reduce the cost of other treatment for these patients, either through primary care or urgent care services.

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Why the committee made the recommendations

Limited evidence was identified on the support prescribers and people may need when making decisions on cannabis-based medicinal products. Some evidence identified the need for training and further education for prescribers, while international guidelines described the overarching support that people seeking cannabis-based medicinal products may need.

The committee agreed that the key theme was the need for prescribers to discuss the risks, benefits and alternatives to cannabis-based medicinal products with people seeking treatment. The committee noted that with the change in legislation people may require licensed or unlicensed medicines, which would also be a key area for discussion. This recommendation should encourage shared decision making and allow people to make informed decisions about their care.

The committee also recommended that prescribers follow the NICE guideline on patient experience in adult NHS services. This has specific recommendations on shared decision making and details the support prescribers can provide when discussing treatment options.

How the recommendations might affect practice

The recommendations promote shared decision making and allow people to make informed decisions about their care. The committee noted that there may be situations in which a multidisciplinary team may help to reach a decision on treatment, such as the care of babies, children or young people. A multidisciplinary team may also need to be involved when decisions need to be made that are in the patient's best interest. This may not be feasible in all specialist care settings because staffing and structure of care provision varies.

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