Review ArticleABSTRACT
Cannabis is used around the world for medicinal, religious and recreational purposes. In 2018, the Argentine Republic approved new legislation, adapting to the provisions of the WORLD HEALTH ORGANIZATION. Law No. 27,350 regulates medical and scientific research on the medicinal, therapeutic and / or palliative use of the Cannabis plant and its derivatives. At the time of this publication, 5 projects were approved for the production of plant material and scientific studies. This work aims to show the results of the latest studies published in the world, on the effectiveness of treatment with medicinal cannabis or cannabinoids, in voluntary patients with chronic pain.
Keywords: Cannabis; Medicinal Use; Pharmaceutical Challenges; Clinical Trials
Introduction
What is pain? We all intuitively understand what it means.
But when trying to quantify, giving it values and intensities, the
subjectivity of each individual comes into play [1]. Pain is one of the
prevalent pathologies worldwide and acquires special importance,
due to the health expenditure it generates [2]. However, that pain is
one of the prevalent pathologies in society around the globe, is an
indicator of a much deeper question that requires another type of
analysis. Usually, the medical doctor uses a scale of values between
1 to 10 as a way to standardize what is not standardized [3]. The
subjectivity with which we perceive the intensity of chronic pain
induces in the human being a state of despair, which influences
all his healing processes. Chronic pain makes the human being
susceptible to contracting diseases, due to the decrease in the
cells of the immune system. Depression and stress, produced by
prolonged states of discomfort and pain, decrease defenses due to
increased synthesis of adrenaline and cortisol [4].
Persistent nociception induces depressive behavior. And its
relationship is made by the enzyme that synthesizes the tryptophan
amino acid [5]. Chronic pain affects the general condition of the
patient and increases the circulation of catecholamines in the blood.
The excess of circulating catecholamines, reduce the concentration
of leukocytes, cells that defend against possible infections,
increasing the risk of contracting diseases. A study made in mice
evaluated the consequences of stress on the quality and quantity
of long-term immune memory. The animals were subjected to
stress through an aggressive event. Later they were inoculated with
herpes simplex virus (HSV). The mice in the stressed group showed
a suppression of the Acs response and a decrease in the memory
of IL-4 and IL-10 synthesis. The mice in the control group, which
had not been exposed to the stressor, showed non-impact on the
immune responses and immune memory [6].
This also creates a vicious cycle that only prolongs pain and the
feeling of discomfort. Studies prove that states of intense pain are
maintained and become chronic due to pro-inflammatory central
immune signaling. Recent findings involve the innate immune
system, known as Toll-like receptors. Toll receptors are involved in
the activation of these pro-inflammatory events that activate pain
pathways through molecular patterns associated with pathogens
or hazards [7]. As a sensory or emotional experience, pain is at
least a cause of discomfort. It can be associated with both tissue
injury and potential damage. Beyond the scales, pain is considered
to exist as long as the patient expresses that he or she feels pain. It
is in any case a subjective concept and exists whenever a patient
says that something hurts [8]. It is a prevalent pathology and that
acquires special relevance among the labor population due to its
socioeconomic implications [9]. A brief comment aside, are deserve
for the analgesics and the chronic consumption that leads patients
to opiate addiction and in many cases to death [10].
The U.S. Centers for Disease Control and Prevention revealed
that overuse of opiates during the coronavirus pandemic killed
nearly 70,000 Americans in 2020, with an agency provisional tally
showing that 93,331 deaths were recorded in 2020, a record and
an increase of 29.4% over the previous year [11]. So is modern
pharmacology the only way to counteract the consequences
on a biological, mental and emotional level that chronic pain
produces? For several years there has been a growing interest in
the general population for alternative therapies that go beyond
treating a symptom, hiding it behind a pill with more side effects
than solutions [12]. In 2018, the Argentine Republic approved
new legislation, adapting to the provisions of the WORLD HEALTH
ORGANIZATION. Law No. 27,350 regulates medical and scientific
research on the medicinal, therapeutic and / or palliative use of the
Cannabis plant and its derivatives. At the time of this publication,
5 projects were approved for the production of plant material and
scientific studies.
An option for the treatment of chronic pain and a palliative for
associated mental and emotional conditions are phytocannabinoids.
So far, 108 phytocannabinoids have been identified from the
Cannabis Sativa and Indica plant [13]. Cannabidiol (CBD) and
Δ9-tetrahydrocannabivarin (THCV) are reported as being of
great clinical interest. Δ9 -tetrahydrocannabinol (THC) is the
phytocannabinoid with the highest affinity for endocannabinoid
receptors in the brain. The cannabis plant uses very similar enzymes
for the synthesis of THC and CBD, so both are C21 terpenophenols
with pentyl alkyl tails [14]. Minewile THCV of C194 propyl tail is
a structural analog. The natural options captured the interest of
the population that seeks the resolution of their diseases, from a
holistic perspective of health and general well-being. Conscious
movement, as the reversion to an ancient therapy that aligns body,
mind and spirit, requires a paradigm shift and an expansion of
therapeutic options [15].
The notorious appearance of patients who choose the alternative
of cannabis treatment as a solution to their ailments is an indicator
of acceptance [16]. Palliative treatments in diseases such as chronic
pain, degenerative diseases, cancer, epilepsy and some of those
classified as mental, such as depression, are just some of the options
offered by this medicinal plant [17-20]. This work aims to update
and contextualize the latest published information on clinical data,
with well-founded protocols considering subjectivity. Without the
intention of defining, which is the ideal classification, it is true
that pain is a subjective appreciation, which involves electrical
thresholds, emotional perceptions, context, duration, mental state,
the individual personality characteristics, who manifests it, among
many other variables. It is also true that cannibinoid treatment is
still prescribed, only in case of failure of other analgesics previously,
that is to say that the pain becomes chronic, while we look for an
efficient palliative. According to a metadata study published in
September 2021 by Wang, et al [21], which sought to establish a
risk-benefit ratio in the prescription of cannabioids and medicinal
cannabis for the treatment of chronic pain.
For the review they used better known scientific databases. The
selected clinical trials consisted of those in which the administration
was following double-blind models. Trials where medicinal
cannabis or cannabinoids were administered for a time equal to
or greater than thirty days, against other analgesics commonly
used in the treatment of chronic pain. A total of 32 clinical trials
were scrutinized, 29 of which used placebo vs cannabinoids or
medical cannabis in the double-blind study. Data from 5174 adult
patients, who were administered the drug or placebo orally in 30 of
the reviewed studies. Only two clinical studies were reviewed and
applied topically. The authors of the metadata review found that
the trials carried out evidence moderate to low analgesia in most
of the sample cases studied. However, it was also reported that a
smaller group of people experienced a significant improvement in
analgesia, pain relief, better sleep quality, and general well-being.
Some limitations of this study mentioned by the authors were:
1) No long-term effects were measured. We found no eligible
trials of chronic pain treatment with medical cannabis that
exceeded 5 months and 5 days.
2) Only a third of the trials chosen for this study, included in their
cohort patients who consumed or are currently consuming
the substance. Volunteers who have consumed other types of
substances were also ruled out, also volunteers with mental
illnesses in 75% of the cases, while the remaining 25% do not
report whether the volunteers with mental illnesses fall within
the cut-off line. Therefore, our conclusions do not reach or may
not be transferable to this group of the population.
3) Third, the high variability between the trials, the subjectivity of
the volunteers, the effects, the reduced numbers of volunteers,
contribute to making some subgroups more visible than
others, minimizing important subgroup effects.
Although the possibility of the use of cannabis as a therapeutic
agent in the treatment of pain is very attractive and opens a plethora
of possibilities, other studies also agree with Wang’s work. Haleem
& Wright 2020 [22] analyzed the effect of a medical cannabis
treatment for pain in older adults. For this, they selected 34 studies
published between 2000 and 2020. Of the selected studies, 30 were
randomized clinical trials (RCTs). They concluded that cannabisbased
drugs are effective in refractory multiple sclerosis therapy.
In case of cancer pain in advanced stages, it was found that relief is
not enough. Encouraging results were found regarding its use for
the control of chronic rheumatic pain. Adverse effects attributed to
a low THC concentration in the samples were reported.
Conclusion
Training is essential for pharmacist, the role of the chemist
in the synthesis of cannabinoids and the accompaniment during
the treatment of the doctor. In this way, users of Cannabis and its
derivatives make informed and safe use. This review only aims to
navigate a sea of unanswered questions and others that, although
answered, need more evidence to shore them up. Further research
is requested on the intensive care setting of medical cannabis and
the relative implications. Pharmacists must explore metabolic
pathways of action and detoxification. Chronic toxicity studies
to know the long-term effect of consumption are also a pending
debt that can be resolved with the application of the new law in
our country [5]. Fundamentally, more studies are necessary, which
consider a larger population. According to a report by the United
Nations Office on Drugs and Crime, 77 countries have reported
an increase in cannabis use during the pandemic. In surveys of
health personnel, the people surveyed, stated that 42% of them use
cannabis.
This represented a marked increase during the pandemic.
These data lead us to rethink the design of clinical trial protocols,
since almost half of the population is excluded. In order to reliably
establish whether medical cannabis or cannabinoids really
represent an advantage over commercial pain relievers, further
research is necessary. A promising future is predicted with the
approval of the first studies with cannabis in the Argentine Republic.
Acknowledgement
National Agency for Scientific and Technological Promotion (ANPCyT), Ministry of Science and Technology (MiNCyT), National Council for Scientific and Technical Research (CONICET).
Conflicts of Interest
Authors declare there is no conflict of interest.
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