cannabis-based medicines & cannabinoids · anabolic steroids, bdz, ghb, gbl, tramadol,...

Dr Fauzia HasnieConsultant Pain Specialist

Guy’s & St. Thomas’ NHS Foundation Trust

Cannabis-based Medicines & Cannabinoids

25th South Thames Acute Pain Group Meeting, London7th November 2019

Outline

Terminology & classification

Overview of cannabis-based products & cannabinoids

Current U.K. licensing

CBD oil

Evidence in pain

Guidance & position statements

Terminology

• Medical cannabis (or medical marijuana) - Cannabis plant (flowers, buds, leaves or full plant extracts) used for medical reasons

• Cannabis-based medicines - Registered medicinal products with manufacturing quality assurance containing cannabis extracts with defined and standardised THC and THC/CBD content

• Cannabinoid - A drug that acts on the endocannabinoid system

• Non-medicinal CBD products - Products containing cannabidiol that are widely sold as herbal remedies/ food supplements but are not regulated as medicinal products (eg. CBD oil)

Cannabinoid Classification

Endogenous

Exogenous

Endocannabinoids(Brain-derived)

e.g. AEA, 2AG

Phytocannabinoids(Plant-derived)

e.g. THC, CBD, CBN etc

(>140 compounds)

Synthetic Cannabinoids (Pharmaceutical lab)

e.g. mimic THC

The Endocannabinoid System:Role in regulation of physiological processes

• Appetite• Metabolism• Mood• Motor function• GI tract function• CVS control• Stress response• Developmental biology• Immune & inflammatory

response• Endocrine function• Neurotransmission & pain

Overview of Cannabis-based Products & Cannabinoids Adapted from Freeman et al.BMJ 2019;365:I1141.

Medicinal Products Non-Medicinal

Products

Plant-derived Synthetic Plant-derived Synthetic

Bedrocan Tilray Sativex Epidiolex Dronabinol NabiloneWhiteWidow

CBDOil

Spice

THC THC THC:CBD CBD THC THC High CBD High THC CB Receptor +/-CBD +/-CBD ratio 1:1 Low THC Low CBD Agonists

Cannabinoid Profile

Formulation

Herbal Oil Oromucosal Oral Capsule Capsule Varied; Capsule Herbal Herbal,Cannabis Spray Solution or Liquid & Oil Cannabis Liquid/ Powder

Licensed Indications (U.K.)

None None MS None None Chemotx- None (not medicinal products -induced n&v no quality assurance

Bedrocan Tilray Sativex Epidiolex Dronabinol NabiloneWhiteWidow

CBDOil

Spice

Yes Yes No No No No No - Not Medicinal Products

Affected by re-scheduling in Nov 2018?

Pre-amendment schedule U.K.

Post-amendment schedule U.K.

1 1 4 Not sched 2 2 Not sched 1 1(if THC <0.2%)

2 2 4 Not sched 2 2 Not sched 1 1(if THC <0.2%)

Can be prescribed in U.K?

Doctors on GMC specialist

register; named patient

basis

Specialist Doctors

with expertise in treating

MS

Likely Specialist

prescribing;named patient

basis

Named patient

basis

Preferably hospital setting

No restrictions on prescribing

No - Not Medicinal Products

Licensed Indications (U.K.)

None None MS None None Chemotx- None (not medicinal products -induced n&v no quality assurance

• A,B,C, Classification based on harm set out by the ‘Misuse of Drugs Act 1971’

• Class A – most dangerous, harshest punishments e.g. crack cocaine, ecstasy (MDMA), heroin, LSD, morphine, methadone, methamphetamine (crystal meth)

• Class B – e.g. amphetamines, barbiturates, cannabis, synthetic cannabinoids, codeine, ketamine, Ritalin, synthetic cathinones

• Class C – least capacity for harm e.g. anabolic steroids, BDZ, GHB, GBL,

tramadol, gabapentin

• Scheduling based on the ‘Misuse of Drugs Regulations 2001’ and level of control governing production, supply, possession, prescribing, record keeping

• Schedule 1 – highest level of control, drugs thought to have no medicinal benefit and high risk of misuse e.g. cannabis, raw opium.

• Schedule 2 – e.g. cannabis-based medicinal products, opiates, methadone, ketamine, cocaine

• Schedule 3 – e.g. gabapentin, pregabalin, midazolam tramadol

• Schedule 4 – Controlled drug prescriptions do not apply e.g. sativex, zopiclone, anabolic steroids

• Schedule 5 – sold over the counter, can be legally possessed without a prescription.

Drug Classes & Scheduleswww.gov.uk/penalties-drug-possession-dealingwww.bnf.nice.org.uk/guidance/controlled-drugs-and-drug-dependence

Current U.K. Licensing

*Currently going through the licensing system

SATIVEXModerate to severe spasticity in MS

• First cannabis-based medicine to be licensed in the UK (schedule 4)

• Derived from whole plant extracts of Cannabis sativa – contains both Δ-9-THC and CBD (ratio 1:1) – 100 microlitre spray contains: 2.7mg Δ-9-THC & 2.5mg CBD

• Oromucosal spray - number of sprays is gradually increased each day until the optimum dose is reached.

• For moderate to severe spasticity in multiple sclerosis (refractory to other treatments)... but NICE does not recommend - not cost effective.

• Prescribed by specialist doctor with expertise in MS

• Side-effects: Dizziness, disorientation, confusion, anxiety, changes in mood, paranoid ideas, hallucinations, delusional beliefs or transient psychotic reactions

NABILONEChemotherapy refractory nausea & vomiting

• Synthetic cannabinoid capsule (schedule 2)

• Mimics Δ-9-THC

• High side-effect profile

• For chemotherapy patients with refractory n&v

• No restrictions on prescribing – preferably administered in a hospital setting. GPs may prescribe once treatment initiated.

EPIDIOLEXRare, severe epilepsy in children

• It is a highly purified liquid containing CBD (no THC)

• Currently in phase 3 trials and going through the licensing system

• For children with rare severe forms of epilepsy (Lennox-Gastautsyndrome and Dravet syndrome)

• No restrictions on prescribing, likely specialist prescribing; named patient basis

CBD (Cannabidiol) Oil

https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.htmlSlide kindly donated by Dr Sadiq Bhayani

Adapted from https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html

HEALS BRAIN INJURY

CURES CANCER

STOPS EPILEPSY

CURES CANCE

R SPEEDS RECOVERY FROM WORKOUTS

LOWERS BLOOD SUGAR

LESSENS ARTHRITIS PAIN

PREVENTS ANXIETY

CALMS DOGS

PROMOTES RECOVERY FROM OPIOID ADDICTION

HEALS PTSD

TREATS CROHN’S DISEASE

SLOWS PARKINSON’S

RELIEVES DEPRESSION

CURBS ANGER

RELIEVES MENSTRUAL CRAMPS

SLOWS ALZHEIMER’S DEMENTIA

HALTS PSYCHOSIS

FIGHTS GRAFT VS HOST DISEASE

REJUVENATES SKIN

HELPS SLEEP

HEALS BRAIN INJURY

Wonder drug?

"For every complex problem there is

an answer that is clear, simple, and

wrong”

H.L. Mencken

CBD Oil ...What is it?

• Cannabidiol extracted from flowers or leaves of marijuana or hemp plants.

• Dissolved in an edible oil (sunflower, hemp or olive oil).

• Contains various concentrations of CBD, THC (<0.2%) and minor cannabinoids – ‘entourage effect’

• Cannabis plants may be contaminated

• Contaminants intentionally added to increase yield or potency e.g. pesticides, synthetic cannabinoids.

• Unintentionally added contaminants eg. heavy metals, moulds and bacteria – end up in a concentrated form in the final oil (including toxic solvents used during extraction)

CBD Oil...How is it made?

• Concentrated solvent extract

• Solvent varies - relatively innocuous organic solvents (ethanol, isopropyl alcohol) to more harmful ones (petroleum-ether, naphtha, butane or CO2)

• Solvent impacts the taste, colour and viscosity.

• ‘Decarboxylation’ - to evaporate solvent and remove acid forms of THC and CBD – poor quality control can result in toxic compounds in final oil

• ‘Winterisation’ (extract is placed in a freezer -20 to -80C for 24-48 hours) –removes other plant components (waxes, chlorophyll) which are co-extracted; these can be removed by filtration or centrifugation.

• Currently, produced without any regulation or quality/ safety assurance.

CBD Oil...Is there a therapeutic effect?...harm?

• Tend to only contain very small amounts of CBD, much smaller than what has been tested in clinical trials – not clear what clinical effect they have.

• Dosed simply by counting the number of drops consumed

• Unknown risks about long-term effects, especially in vulnerable groups (children , elderly, chronically or terminally ill).

• Potential for drug interaction?

Evidence for Use in Chronic Non-Cancer Pain (CNCP)

• Systematic review: Included any study reporting on any cannabinoid for anyCNCP condition, measuring at least one pain outcome up to July 2017

• Examined efficacy of cannabinoids for CNCP using *IMMPACT outcomes: – pain intensity (30% & 50% reduction in pain)

– physical functioning

– emotional functioning

– global impression of change

– adverse events

* IMMPACT: Initiative on Methods, Measurement and Pain Assessment in Clinical Trials

E. Stockings et al. Pain 159(2018) 1932-1954

Study CharacteristicsE. Stockings et al. Pain 159(2018) 1932-1954

• 104 Studies (n = 9,958) – mix of 47 RCTs; 57 Observational• Pain condition:

– 48 NeP (16 MS-related; 32 non MS-related)– 7 Fibromyalgia– 1 RA– 48 Mixed CNCP (13 MS-related; 29 non MS-related; 6 Visceral pain)

• Cannabinoids used: – 26 Cannabis sativa– 24 Nabiximols– 18 Dronabinol– 17 Nabilone– 11 THC extract – 3 THC:CBD extracts– 2 CBD extracts– 1 THC-HS– 1 unknown/ not stated

• Formulation and route of administration varied depending on type of cannabinoid used– smoked cigarrette, oral mucosal spray, pill/ capsule or oil.


Odds ratio 1.46 = Increased likelihood that people with NeP & CNCP receiving cannabis/ cannabinoids would achieve a 30% reduction in pain


RESPONSE RATE: 29% of people using Cannabinoids experienced a 30% reduction in pain vs. 25.9% Placebo

‘Number Needed To Treat’ (NNT): 24 (15 to 61)


All studies looking at a 50% reduction in pain were conducted in NeP conditions.

Odds ratio 1.43 (0.97-2.11) = Although odds ratio is greater than one, the confidence interval includes zero and therefore crosses

the line of no effect.


RESPONSE RATE: 18.2% of people using Cannabinoids experienced a 50% reduction in pain vs. 14.4% Placebo – this difference is not significant.

Unable to calculate a NNT to benefit as CI crosses zero.


Standardised mean difference: -0.14 = favours a reduction in pain intensity (largely led by participants with NeP conditions)

When re-expressed, it is equivalent to a 3mm reduction on a 0-100mm VAS.


No impact on emotional functioning, physical functioning or QOL

Small improvements in sleep


Unlikely that cannabinoids are highly effective medicines for CNCP.

NNT were high

Small reductions in pain for certain CNCP conditions but minimal to no improvement in other important domains in people living with CNCP.

High rates of dropout for adverse events.

• EFIC Task identified 15 systematic reviews (2009-2018) & 5 guidelines from scientific societies and national agencies (2014-2018).

• Expert opinion/ experience ? biased

• Medical cannabis vs cannabis-based medicines

– Insufficient evidence as to whether they differ in their efficacy, tolerability and safety.

Findings & recommendations for chronic NeP pain:

Cannabis-based medicines can be considered as 3rd - line for chronic neuropathic pain (in view of NNT for pain relief of 30% & NNH)

Mücke et al. 2018

• 16 Studies; 2-26 weeks duration; n=1750

• Sativex (10)/ nabilone (2)/ inhaled herbal cannabis (2)/ dronabinol (2) vs. placebo (15)/ dihydrocodeine (1)

• Study quality: low (2); moderate (12); high (2)

No high quality evidence that any cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC) was of any value in treating people with

chronic NeP pain.

Potential benefits (NNT 11) might be outweighed by the potential harms (NNH 25).

“Beware of false knowledge, it is more dangerous than ignorance”

Findings & recommendations for chronic non-cancer,non-NeP pain:

There is insufficient evidence.

In exceptional cases, cannabis-based medicines can be considered as an individual therapeutic trial, if all established treatments have failed and after careful analyses and multidisciplinary assessment.

Can I get a prescription for medical cannabis?

How might cannabis help me?

What about products available to buy?

Is medical cannabis safe?

What are the side-effects?

Will the laws on cannabis be relaxed?

U.K. Guidance & Position Statements

Pending:

• NICE Guidelines ‘Prescribing of cannabis-based products for medicinal use’ in development - expected publication date: 11th November 2019:

• IASP Cannabis & Cannabinoids Task Force – aims to review & evaluate current clinical evidence for the benefits & harms of cannabinoids as analgesic drugs

Interim:

• NHS patient information

• NHS England/RCP Interim guidance on prescribing cannabis-related products (Oct 2018)

• BPS position statement

• FPM RCoA position statement

https://www.nice.org.uk/guidance/indevelopment/gid-ng10124

1.2 Chronic pain

1.2.1 Do not offer the following to manage chronic pain in adults:

• Nabilone

• Dronabinol

• THC

• a combination of CBD with THC

1.2.2 Do not offer CBD to manage chronic pain in adults unless as part of a clinical trial.

https://www.nice.org.uk/guidance/indevelopment/gid-ng10124

• Some evidence that cannabis-based medicinal products reduce chronic pain but the treatment effect was modest (average improvement of 0.4 on a scale of 0-10).

• The evidence did not show a reduction in opioid use in people prescribed medicinal cannabis.

• Potential benefits offered were small compared with costs – not an effective use of NHS resources.

• No evidence for the use of CBD alone.

• No evidence for intractable cancer-related pain or pain associated with painful childhood diseases.

• Research recommendations for clinical & cost effectiveness of CBD in adults with fibromyalgia or treatment-resistant NeP.

NHS Patient information (1)www.nhs.uk/conditions/medical-cannabis

• Cannabis is a class-B illegal drug in the UK

• Government not planning to legalise cannabis for recreational use

• Possessing cannabis is illegal, whatever you're using it for.

• Some evidence medical cannabis can help certain types of pain, though this evidence is not yet strong enough to recommend it for long-term pain relief.

NHS Patient information (2)www.nhs.uk/conditions/medical-cannabis

• Cannabis-based products over the internet – their quality and content is not known, likely to be illegal and potentially dangerous

• They may also contain THC

• Potential for drug interaction

• Health stores sell certain types of "pure CBD” or “CBD Oil” – but no guarantee these products will be of good quality.

• Contain very small amounts of CBD – not clear what clinical effect they have.

• The main risks of THC cannabis products are psychosis and dependency

Interim guidance from RCP on cannabis-based products for medicinal use (CBPM) in pain (1)

Key recommendations in Chronic Pain...

There is no robust evidence for the use of CBPM in chronic pain and their use is not recommended.


Key recommendations in Chronic Neuropathic Pain...

Cochrane review (March 2018): ‘There is a lack of good evidence that any cannabis-derived product works for any chronic neuropathic pain... the potential benefits of cannabis-based medicine in chronic neuropathic pain might be outweighed by their potential harms.’

A comprehensive meta-analysis of pharmacotherapy for neuropathic pain (The Lancet Neurology in 2015) – accessed unpublished trials: It recommended against the use of cannabinoids in neuropathic pain, mainly because of negative results, potential misuse, diversion, and long-term mental health risks of cannabis particularly in susceptible individuals. Only 2 of 9 trials of Sativex in neuropathic pain were positive.

National reports from the USA, Australia and Ireland all comment on the lack of good quality evidence regarding short and long-term outcomes for both benefit and harm...potential parallels with widespread use of high-dose opioids


Key recommendations in Palliative care...

There is limited research available from which to create guidance on the effect of CBPM on pain in palliative care patients. Studies show mixed results or statistically significant results of uncertain clinical significance.

In view of this and the adverse effects associated with CBPM, their place in the treatment of pain in palliative care patients is unclear and not recommended in routine clinical practice.

BPS Position statement (1)

The British Pain Society welcomes the increasing awareness and changes in government policies towards the potential use of cannabinoid preparations for the management of various chronic medical conditions including epilepsy, multiple sclerosis and pain management. Members of The British Pain Society have occasionally come across patients who have benefited from using cannabis and acknowledge that it may have a place in pain management for a small number of carefully selected people. However, meta-analyses of clinical studies on cannabinoids for the management of pain conclude that there is no positive evidence to support routine use in pain management. These include neuropathic pain, chronic non-malignant pain and cancer pain.


The British Pain Society acknowledges that the quality of some studies is not of a high standard and supports the need of well-designed robust clinical trials and registries to evaluate the safety, efficacy and harms of cannabinoid preparations in pain management.

In the meantime, any use of cannabinoid preparations for pain management should be closely monitored for benefit and side-effects; these findings should be evaluated within a national database and any concerns should be appropriately investigated.


Currently, there is a paucity of effective analgesics that could be safely used in the long term without deleterious side-effects and this highlights the need for analysing the scope of medical cannabis in the management of chronic pain through scientific rigour, rather than extrapolating findings following recreational use of cannabis products.

There are a wide variety of cannabinoid products available with varying composition of active ingredients with different potencies and doses; hence there is a need for close monitoring to ensure safety for people prescribed cannabinoid medicines.


The British Pain Society considers there may be a role for medical cannabis in pain management, but more reliable evidence is warranted following robust clinical evaluation.

In the meantime, a short therapeutic trial of cannabis should be only considered when established treatment options have not provided sufficient efficacy and tolerability, and it is clinically justified for an individual person.

Appropriate clinical surveillance should be carried out for the duration of treatment with cannabinoids in a multidisciplinary pain service with the relevant clinical expertise. Treatment goals should be defined and as with other therapy, medical cannabinoids should be withdrawn if there is failure to achieve therapeutic benefit and/or in the presence of adverse effects and/or there is evidence of abuse or misuse.

FPM Position statement on the medicinal use of Cannabinoids in Pain (1)

...potential parallels with widespread use of high dose opioids in the absence of good long-term evidence...

...the Faculty considers that the issue of cannabinoids needs to be carefully considered and researched in a comprehensive fashion, as would be the case for any new medicinal product reaching the therapeutic market, and that anecdotal positive reporting is not a mechanism to protect public safety.

We therefore feel that further high quality research is mandated in view of potential benefit...If there are specific patient populations that will benefit, they should not be denied access when the evidence is available.


The use of unrefined dried plants containing a variety of cannabinoids and other pharmaco-active chemicals of varying quantity cannot be supported and is clearly contrary to the direction of medical science.

The potential for exposure to significantly harmful chemicals, in the short or long term, by such an unscientific ‘herbal’ approach is of considerable concern, as is diversion to non-medical use. Therefore, only products produced to pharmaceutical standards should be considered.


The Faculty supports the setting up of robust trials or database to look at potential benefits in pain...database to be independent, compulsory, fully funded and under the auspices of a suitable organisation (e.g. NICE)

Any use of cannabinoids for pain management should only occur after conventional interventions have failed and then only within the confines of a limited number of secondary care multidisciplinary specialist pain services, with all cases being nationally audited.

The Faculty would wish to be directly involved in the establishment of guidance and data collection which impacts on the management of pain.

Take Home Messages

• Be clear on terminology

• Cannabis is ilegal

• Currently, only Sativex and Nabilone is licenced in U.K.

• CBD Oil is not available on prescription.

• CBD Oil - ? quality ? safe ? clinical effect.

• Unlikely that cannabinoids are highly effective medicines for CNCP (NNTs high) - evidence divided for NeP CNCP.

• Further high quality research is needed.

• Potential parallels with widespread use of high dose opioids.

References

• Bhandari S and Menon R ‘Cannabinoids: Where are we?’ RCoA Bulletin Issue 117 September 2019:12-13. • Campbell G et al. ‘Understanding the evidence for medical cannabis and cannabis-based medicines for the

treatment of chronic non-cancer pain’. Eur Arch Psychiatry Clin Neurosci. 2019 Feb;269(1):135-144.• Deshpande A and Chatziperi A ‘Medicinal cannabis in Canada: potential lessons from across the pond’. BPS

Pain News. June 2019 Vol 17 No 2 p.68-71.• Freeman et al. ‘Medicinal use of cannabis-based products and cannabinoids’. BMJ 2019;365:I1141.• Hande K ‘Cannabidiol – The need for more information about its potential benefits and side effects’. Clinical

Journal of Oncology Nursing April 2019. Vol 23 No.2 p.131.• Harrison et al. ‘Clinician’s guide to Cannabidiol and Hemp Oils’. Mayo Clin Proc. September 2019;94(9):1840-

1851.• Hāuser W et al. ‘European Pain Federation (EFIC) position paper on appropriate use of cannabis-based

medicines and medical cannabis for chronic pain management’. Eur J Pain. 2018 Oct;22(9):1547-1564.• Hazekamp A ‘The trouble with CBD oil’. Med Cannabis Cannabinoids 2018;1:65-72.• Stockings E et al. ‘Cannabis and cannabinoids for the treatment of people with chronic non-cancer pain

conditions: a systematic review and meta-analysis of controlled and observational studies’. Pain. 159(2018):1932-1954.

• Mücke M et al. ‘Cannabis-based medicines for chronic neuropathic pain in adults’. Cochrane Database of Systematic Reviews March 2018 https://doi.org/10.1002/14651858.CD012182.pub2.

• NICE Guideline draft for consultation, August 2019 ‘Cannabis-based medicinal products’• Ware M A and Desroches J ‘Medical cannabis and pain’. IASP Pain Clinical Updates Vol XXII No.3 October

2014.• Royal College of Physicians ‘Recommendations on cannabis-based products for medicinial use’ October

2018. • Zou S and Kumar U ‘Cannabinoid receptors and the endocannabinoid system: signaling and function in the

central nervous system’. Int J Mol Sci. 2018;19: 833.

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