Cannabis for neuropathic pain in multiple sclerosis - high expectations, little data
Introduction
The pain affects about two-thirds of people with multiple sclerosis (MP). Pains associated with MS include headaches (43 %), neuropathic pains in arms or legs (26 %), back pains (20 %), painful cramps (15 %) and pains of the trigeminal nerve (3.8 %). The prevalence of neuropathic pains in patients with MS, which arise from the damage of peripheral or cranial nerves, described by the ill as “the worst from all tortures which damage of nerves can cause”, dramatically reduce the quality of diseased patients’ lives.
The spot prevalence of neuropathic pain in these patients is nearly 50 %, and approximately 75 % of patients claim that they experienced the pain within one month from its evaluation. The pharmacological treatment of neuropathic pain related to MS resides in the use of tricyclic antidepressants, anti-epileptic drugs, Baclofen, anaesthetic and antiarrhythmic drugs. These procedures have usually unsatisfactory results and often carry severe side effects. It is crucial to notice that insufficient therapy of neuropathic pain is one of the components contributing to the opiate crisis in the USA, and it is thus essential to use alternative methods of relief from neuropathic pain.
Many reports from patients show that cannabis and its main cannabinoid components have propitious effects on pain in people diseased by illness MS, particularly on neuropathic pain. These reports are, however, supported by the little scientific evidence. Results of many tests agree that cannabis could have a positive effect on pain due to MS. Unfortunately, the majority did not address questions of experiment quality and comprise various medications, doses, duration of their administration, test conditions and results. Several questions concerning cannabis use due to neuropathic pain treatment in MS remain unsolved.
Therapeutic cannabis - use, form and administration
The term “cannabis” is often used in media and politics and includes all drugs based on the cannabis plant Sativa. Its hundreds of compounds, such as delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) extracted from cannabis and analogues of THC. THC shows psychoactive effects, and it can cause acute psychosis and influences the functioning of an individual. CBD is not psychoactive like THC and it emerged that it is emotionally beneficial (anxiolytic), anti-inflammatory and neuroprotective. A recent study showed that although CBD can reduce some adverse side effects related to THC use and increase its therapeutic effectiveness, presence of CBD can augment plasmatic concentration of THC metabolite and delicately worsen cognitive functions in comparison with THC itself. These results can have significant impacts on patients with MS using therapeutic cannabis containing both THC and CBD. Estimations indicate that approximately 50 % of MS patients in the USA use cannabis to symptoms relief, but only 48 % of users own patient card. Among MS patients, a widespread unlicensed and often illegal use of cannabis exists which comprises its various forms (e.g. different ratios of THC content). CBD and methods of use (e.g. smoking, eating). In addition, the effects of different cannabis products varied, in which case pure THC products show very distinct effects than products combining THC / CBD. It is not appropriate to transform the effectiveness of one type of cannabis (e.g. with a high content of THC) to another (e.g. with a high content of CBD) or connect their effects. The majority of tests, unfortunately, do not distinguish between different ratios of active substances, and it is not right to draw any conclusions about the effectiveness of cannabis on neuropathic pain. These surveys also included clinical studies with more controlled forms of cannabis, such as Dronabinol or Sativex.
Pains associated with MS
The incidence of pain in MS occurs between 29 and 86 %. Because many subjective variables exist, such as current psychological condition, condition of cognitive functions and environment, which can influence the identification of the pain scale, there are no genuinely objective methods of measuring this highly subjective experience. The pain is, however, related to the reduced quality of life associated with health and disorders of the physical and emotional functioning. Many types of pain associated with MS exist, including neuropathic (persistent or intermittent), musculoskeletal and mixed neuropathic and other than neuropathic pains. Many studies of cannabis focused on neuropathic pain in patients with MS. Restrictions of these studies include methods thanks to which neuropathic pain was diagnosed and defined, subjective character of the estimation of pain. Nowadays, unified diagnostic criteria for a definition of neuropathic pain do not exist. The majority of studies rely on a list of typical characteristics of central neuropathic pain or diagnosis of pain disorder by a doctor after the elimination of causes associated with nociceptive and peripheral pain. Determination of cannabinoids individually treat central element of neuropathic pain, or peripheral causes of neuropathic pain is therefore difficult.
Syndromes of chronic pain differ in symptoms and biophysical mechanisms. Some researches of pain in MS disease included all accessible controlled studies addressing all forms of chronic pain. This approach is problematic for several reasons. Firstly, syndromes of chronic pain (neuropathic, nociceptive and musculoskeletal) can differ in their biophysical mechanisms and symptoms. Secondly, a comprehensive analysis of all pain syndromes without a subgroup analysis of pain syndromes/mechanisms provides doctors and scientists with insufficient guidance as to which particular cannabis product (e.g. THC / CBD ratio) should be used for a clinically defined pain syndrome. Overview of researches included 11 results providing date from 32 studies and showed that cannabis was the effective due treatment of pain associated with MS. However, because this overview did not distinguish among various forms of pain, cannabis products or methods of administration, it is methodologically incorrect to conclude about any effectiveness of cannabis due relief of neuropathic pain in patients suffering from MS. Neuropathic pain can have many dimensions and cannabis can be useful for some forms of chronic illnesses but not for all.
Statistical vs clinical values
Another noteworthy problem is that none of the re-examinations of cannabis influence on pains associated with MS did confirm the clinical importance of statistical results. The clinical and statistical significance of the findings should be considered when evaluating the validity of a study. Studies which show statistically significant differences in two therapeutic options can lack practicality and studies which claim that is relevant for clinical significance can lack sufficient statistical significance to make a meaningful conclusion from them. Doctors and research workers should not only focus on specific statistical values to decide if treatment by cannabinoids is clinically useful. It is crucial to consider the extent of differences in treatment and also the extensiveness of study.
Funding
Due to the required number of patients and the duration of the study, clinical trials concerning cannabis and multiple sclerosis are expensive. Thus, it is not surprising that many of these studies are funded by pharmaceutical companies. Unfortunately, publications of negative results in examined medication reported to sponsor are not available. However, this problem occurs also in many other types of research on medications, and it is not the only exception in treatment based on cannabis.
Safety and duration of the study
Safety and potential long-term effects of cannabis products in patients with MS have not been sufficiently evaluated. All existing studies of MS were short-term, and their duration ranges from 6 to 15 weeks. It is not possible to notice long-term risks and rare, but severe side effects in such short-term studies. Another unique element is the fact that the standardized method to compare profiles of undesirable effects among various forms of cannabis (i.e. different ratios of THC:CBD content) does not exist. It is also difficult to assess if specific undesirable effects are dependent on the dosage, which signifies another critical problem for future studies.
Levels of THC and THC:CBD ratio in cannabis have increased in the last two decades in the USA and Europe, which can raise potential damage due to the repeated use. It is well known that cannabis, particularly products with a high content of THC, negatively disturb cognitive and affective functions in healthy adults and can increase the risk of schizophrenic psychosis or other serious mental diseases. This has significant implications for patients with MS using therapeutic cannabis, as they are more likely to have cognitive aggravation. Psychological impacts of long-term use of cannabis could further increase the risk of health damage in patients with MS and lead to the development of psychosis or severe mental disorders. It is not currently known how using cannabis with any THC:CBD ratio influences patients with chronic pain.
In the report WHO, from 2016, about health and social impacts of cannabis use from other than medical reasons, it is claimed that cannabis can be a factor of undesirable cardiovascular problems, including those leading to death. Cardiovascular effects of cannabis rely on several factors, including the composition of the cannabis product. It is possible that cannabis products with a higher relative quantity of CBD can be safer than products which have none or only low content of CBD. However, it still must be more specified, because only a few laboratories investigate the occurrence of CBD due to toxicology of blood. From this reason, a reduction or even complete exclusion of THC from cannabis extracts used in the treatment of neuropathic pain in MS can be justified from a cardiovascular point of view.
Not even CBD use is entirely without any risk and can provoke interactions with medicaments, for example. A recent review has confirmed and extended the findings from the previous review on the favourable safety profile of CBD. However, different areas of research of safety while using CBD should be expanded, and most importantly, long-term figures about safety are necessary to fully appreciate the balance between benefits and adverse effects of CBD use.
Interaction with other medicaments
A wide range of medications is used due to the treatment of MS. It concerns drugs modifying disease, corticosteroids and other substances which focus on specific symptoms and health issues associated with MS, such as depression, problems with bladder, spasticity, sexual problems, fatigue, pain and emotional changes. Increasing the use of therapeutic cannabis due to symptoms associated with MS, such as pain and spasticity, can cause potential interactions with medications used due to other symptomatic treatment. The majority of known interactions can be found in prescriptions for providers of authorized curative products based on cannabis (Dronabinol and Sativex). However, this information is not available for therapeutic cannabis with various contents of THC / CBD. In addition, there is a lack of figures about possible interactions between synthetic cannabinoids and cannabis, but their combination can increase psychopharmacological activity.
Conclusion
Between cannabis and use of opiates in the past and nowadays, the “painful” parabola exists, when the short-term demonstration of effectiveness on chronic pain lead to adoration and wide prescribing of opiates without quality researches. Absence of any clinically relevant pieces of evidence about beneficial effects of cannabis in the majority of systematic researches and lacking observation of side effects including concerns from impacts of long-term use should be the reason for doctors to stop recommending the use of cannabis due to the treatment of neuropathic pain in patients who have multiple sclerosis.