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Sativex ® improves pain control in patients with unresponsive and persistent neuropathic pain

Chronic neuropathic pain is treatable by local anesthetics, antidepressants, antiepileptic drugs and opioids, but unresponsiveness and treatment resistance are common. According to a new study, better pain control might be achieved by adding Sativex ® (GW Pharmaceuticals, Salisbury, UK) to the existing stable analgesia regime. This drug, derived from extracts of selected strains of cannabis plants (Cannabis sativa), contains the active cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and can be administered as a sublingual and oropharyngeal spray.

Nurmikko et al. performed a randomized, double-blind, placebo-controlled trial to evaluate oromucosally administered Sativex ® in 125 patients with neuropathic pain of peripheral origin, over a 5-week period. The patients all had unresponsive and persistent pain despite therapy. In total, 63 patients were assigned Sativex ® and 62 were assigned a placebo spray: patients self-administered their spray, with a maximum of 48 doses allowed in 24 h, and all remained on their existing stable analgesia during the trial.

Among those receiving Sativex ® , 26% reported a reduction in pain intensity of >30%, which is generally considered as clinically meaningful. Only 15% of patients taking placebo reported a reduction of >30%. Patients taking Sativex ® also showed significant reductions in allodynia and disability and an improvement in sleep patterns compared with patients receiving placebo.

The authors conclude that Sativex ® can provide effective relief of peripheral neuropathic pain when given in addition to existing medication. They noted that the results were particularly encouraging given the refractory nature of the pain among the patients in their study group.

Sativex (nabiximols)

Sativex (nabiximols) is the first cannabis-based medicine to be licensed in the UK. The drug can be prescribed for the treatment of MS-related spasticity when a person has shown inadequate response to other symptomatic treatments or found their side effects intolerable. Sativex can be used in addition to a person’s current anti-spasticity medication.

Prior to gaining a licence for use in MS-related spasticity, Sativex had been studied for its effects on a number of MS related symptoms including: pain, bladder symptoms, tremor, and sleep disturbance.

How do I take Sativex?

Sativex is a mouth (oromucosal) spray containing two chemical extracts derived from the cannabis plant: delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The number of sprays is gradually increased each day until the optimum dose is reached. This can take a few days or up to two weeks. The number of sprays needed varies between different people. The idea is to find the right number of sprays for you, which gives you good relief from your muscle stiffness but with the fewest side effects.

Side effects and contraindications

Common side effects include dizziness, drowsiness, constipation or diarrhoea, fatigue, memory or concentration problems, and a dry mouth or changed sense of taste. These side effects are more likely when you first start treatment and usually wear off within a few days. Speak to a health professional if you experience side effects as there may be steps you can take to minimise them.

Sativex is not recommended for pregnant women and people under 18 years old. People with a history of psychotic problems should not take the drug.

Driving and using machines

Sativex may impair the mental and/or physical abilities required for certain potentially hazardous activities such as driving a car or operating machinery. Driving or using machinery when you first start taking Sativex is not recommended until you are established on a stable daily dose.

If you experience any significant side effects once you’ve established a stable dose, you should not drive, operate machinery or take part in any activity that could prove hazardous.

If you are concerned about the rules around drug driving for people taking prescription medications like Sativex, speak to your health professional. There is also information on the GOV.UK website.

A study in 2018 looked at the effects of Sativex on driving ability in people with MS. It found that, if side effects such as dizziness and drowsiness were not experienced, Sativex did not impair driving. They found no evidence of an increase in motor vehicle accidents associated with taking Sativex. The majority of people in the study reported improvement in driving ability; this was thought to be because of reduced spasticity.

Being prescribed Sativex

Sativex is a licensed treatment and can be prescribed legally in the UK, but NHS prescribing remains very limited and varies across the country. An MS Society report published in August 2021 has highlighted barriers to accessing Sativex across the UK.

England

The NICE guideline on cannabis-based medicinal products recommends that, providing the local NHS health authority (clinical commissioning group, or CCG) is willing to pay for continued treatment, a 4-week trial of Sativex can be offered to people with moderate to severe MS-related spasticity which has not improved while taking other treatments. At the end of the trial, if their spasticity-related symptoms are reduced by at least 20%, they can continue taking Sativex.

Despite this recommendation, many people in England who meet the medical criteria are unable to try Sativex because the local CCG is not willing to pay for continued treatment. There are multiple reasons for this: the CCG may not have revisited local funding decisions in the light of the 2019 NICE guideline; the CCG may not agree with the NICE assessment of cost-effectiveness; the positive impact that small improvements in spasticity symptoms can have on care and quality of life for people with MS and their carers may not be recognised; in many areas of England, there is a lack of appropriate pathways for assessing spasticity or handing over responsibility for prescribing Sativex from hospital consultants to GPs.

CCGs publish decisions about funding of medicines in an online drug formulary; contact your CCG for information about local drug formularies.

Wales

Sativex has also been recommended as a treatment option within NHS Wales for moderate to severe spasticity in people with MS who haven’t responded to other anti-spasticity medication. Lack of published hospital prescribing data in Wales makes it difficult to assess whether the number of people in Wales who are able to access Sativex are at anticipated level.

Scotland

Sativex is not recommended for use within NHS Scotland. The drug manufacturer, GW Pharmaceuticals, plans to apply to the Scottish Medicines Consortium for approval in 2021. Individual doctors may be willing to prescribe without SMC approval.

Northern Ireland

In Northern Ireland, Sativex has been accepted for use as a treatment option (search for Sativex) for people with moderate to severe spasticity who have not responded well enough to other treatments.

Private prescriptions

Limited access to Sativex on the NHS means that some people decide to obtain a private prescription and pay the full cost of the drug themselves. This can be an expensive option and it’s therefore not feasible for everyone.

Legal status of Sativex

As Sativex is cannabis-based, it is a controlled drug. Controlled drugs are given a Class (A, B or C) which reflects their potential for harm and the legal implications for inappropriate supply and possession. They are also given a Schedule which indicates how it can be prescribed and stored.

Sativex is a Class B controlled drug under the Misuse of Drugs Act 1971 and is placed in Schedule 4 to the Misuse of Drug Regulations 2001.

As Sativex is placed in the less-restrictive Schedule 4, this means that it can be prescribed legally in the UK with no restrictions on supply, recording, storage or destruction. ​It can only be prescribed by a specialist doctor with experience of treating MS spasticity – consultant neurologists, consultant rehabilitation specialists and consultant pain specialists.

Use of Sativex is currently limited to those people who respond to the first four weeks of treatment. If there is no clear improvement in spasticity-related symptoms, treatment is stopped.

In November 2018, the legal status of cannabis was amended to allow specialist clinicians to legally prescribe cannabis-based medicinal products to people with an exceptional clinical need.

Research

Clinical trials have shown that Sativex is an effective treatment for MS spasticity. Since being licensed, a number of studies have been published more recently that analyse real-world data on Sativex. Studies have also investigated its potential to treat other symptoms.

One study collected real-world data from 30 MS centres in Italy and included 1,597 people with MS who had started treatment with Sativex for spasticity. The focus of the study was to look at how many people stopped taking Sativex and why. Researchers found that around 4 in 10 people stopped treatment either because it wasn’t effective (2.3 in 10) or because of side effects (1.6 in 10). The most common side effects were cognitive and psychiatric effects – including memory, cognition and attention problems, and panic attacks, hallucinations and depression – fatigue and drowsiness. This suggests that, although Sativex may help with MS spasticity for some people, it may not be effective or suitable for everyone.

Another paper analysed data from a registry which was set up following the approval of Sativex in the UK, Germany and Switzerland. Doctors that were prescribing Sativex were able to record data in the registry. It contains data from 941 people who were prescribed Sativex. The data shows that approximately 8 in 10 people benefitted from treatment, 6 in 10 continued treatment and approximately 3 in 10 people stopped treatment because of lack of effectiveness or side effects. The most common side effects were dizziness and fatigue, and people were more likely to experience these during the first month of treatment.

Studies looking at the effectiveness of Sativex in treating neuropathic pain have been mixed. There’s currently with not enough high quality evidence proving that it’s effective in pain management.

Find out more

  • Patient Information Leaflet – Sativex – (EMC website)
  • GOV.UK – information on drugs and driving law
  • All Wales Medicines Strategy Group – Sativex recommendation, August 2014
  • NICE Guideline Cannabis-based medicinal products – Sativex recommendation, November 2019
  • Scottish Medicines Consortium – unable to recommend Sativex, April 2011

References

  • Sastre-Garriga J, et al. THC and CBD oromucosal spray (Sativex(®)) in the management of spasticity associated with multiple sclerosis. Expert Review of Neurotherapeutics. 2011; 11(5):627-637. Summary
  • Novotna A, et al; the Sativex Spasticity Study Group. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. European Journal of Neurology 2011; 18(9):1122-1131. Summary
  • Kavia R, et al. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Multiple Sclerosis 2010; 16(11): 1349-1359. Summary
  • Collin C, et al. A double-blind randomized placebo-controlled parallel-group study of Sativex in subjects with symptoms of spasticity due to multiple sclerosis. Neurology Research 2010; 32 (5): 451-459. Summary
  • Collin C, et al. Randomised controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. European Journal of Neurology 2007; 14: 290-296. Summary
  • Messina S, et al. Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study). PLoS One 2017;12(8):1-10. Full article
  • Patti F, et al. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. Journal of Neurology, Neurosurgery and Psychiatry 2016;87(9):944-951. Full article
  • Canadian Agency for Drugs and Technologies in Health. Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines. Ottawa: CADTH; 2016. Full article
  • Celius EG, et al. The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity. Brain and Behaviour 2018;8(5):e00962. Full article
  • Etges T, et al. An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland who have been prescribed Sativex® (THC:CBD, nabiximols) oromucosal spray. Therapeutics and Clinical Risk Management 2016;12:1667-1675. Full article

Cannabis

Cannabis is a naturally occurring drug made from parts of the cannabis plant.

Medicinal cannabis

From 1 November, medicinal cannabis can be prescribed by specialist doctors. We look at what is meant by medicinal cannabis, how legislation is changing and what this means for people with MS.

Spasticity and spasms

Spasticity is a symptom of MS where the muscles feel stiff, heavy and difficult to move. A spasm is a sudden stiffening of a muscle.

Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine

Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients’ quality of life.

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