Key words
cannabis-based medicines - chronic pain - chronic stress - central sensitization - nociplastic pain
Introduction
Chronic pain, i. e., pain lasting longer than three months, is a common
health problem that affects quality of life and is a major burden for society [1]. As an epidemiological analysis in Germany
has shown, one can speak of an independent pain disease, especially when chronic
pain is associated with considerable emotional distress and functional impairment
[2]. This definition corresponds to the
current ICD-11 classification of chronic primary pain [3].
A recent review found that a wide range of adverse childhood experiences is
associated with the development, severity, and impact of chronic pain in adulthood
and that the more severe the adverse experiences, the stronger this effect [4].
Stress in early life can interact with genetic factors, especially in vulnerable life
periods, and, involving epigenetic mechanisms, creates the basis for permanently
impaired responsiveness of allostatic systems and thus increases the likelihood of
chronic pain occurring later in life [5]
[6]
[7]. A
significant example of such a process is the epigenetic dysregulation of central
glucocorticoid receptors, resulting in a disruption of stress processing [8]. Both over- and under-activation of the
hypothalamic-pituitary-adrenocortical axis can lead to imbalances in other systems,
particularly the endocannabinoid (EC) [9] and
cortico-mesolimbic systems [10]
[11]. Dysfunction of the cortico-mesolimbic
systems can be understood as a central neurobiological correlate of chronic pain
[10]
[11]
[12], which may remain active
even in the absence of sustained nociceptive input [11]. Trauma in childhood also appears to directly affect pain sensitivity
through epigenetic changes in ion channels such as the transient receptor potential
ankyrin-1 channel (TRPA1) [13]. This fits with
the observation that stress in early childhood is associated with the development of
pro-inflammatory responsiveness throughout life [6], e. g., via priming of microglia [14]
[15].
Overall, the above-mentioned changes can be understood as an expression of central
pain sensitization, which involves intensified neuronal signaling in the central
nervous system (CNS), resulting in pain hypersensitivity, clinically manifested in
diffuse, widespread pain disproportionate to what would be expected based on the
available presumed source of nociception [16].
A pain intensity above 40 out of 100 on the Central Sensitization Inventory (CSI) is
required to determine central pain sensitization [16]. The CSI maps a variety of biopsychosocial aspects, fitting to the
multidimensional character of chronic pain, which includes e. g.,
generalized sensory sensitivity, increased somatic perception, cognitive impairment,
and sleep problems [17]. These factors have
been included into the new pain classification “nociplastic pain” of
the International Association for the Study of Pain [16]. A recent review of studies on central sensitization in chronic low
back pain showed that these factors correlate with psychosocial characteristics such
as depression, anxiety, and somatization [18].
The development of chronic pain associated with traumatic life events can also be
understood based on central pain sensitization [19]
[20]. In a cross-sectional study
of 202 patients with chronic pain, both traumatic events and PTSD symptoms were
significantly associated with clinical indicators of central sensitization, such as
pain severity, pain intensity, and polysomatic complaints measured by the CSI [21]. Patients with PTSD who did not report pain
showed higher pain scores and significantly increased temporal summation after an
intramuscular capsaicin stimulus compared with control subjects, indicating an
increased vulnerability to pain sensitization [22]. In a cohort of 914 patients with chronic pain from a German
university hospital outpatient clinic, positive correlations were found between
observed intensity of trauma and pain area overlap, pain widespreadness, maximum
pain, sleep disturbance, pain disability index, stress, anxiety, depression, and
somatization [23]. The increased pain area and
pain widespreadness, as well as the effects on clinical endpoints such as pain
intensity, sleep disturbance, symptom burden disability, and stress, are consistent
with the concept of central sensitization in patients with PTSD [23].
Central pain sensitization and the endocannabinoid system (ECS)
Central pain sensitization and the endocannabinoid system (ECS)
Preclinical studies have shown that proinflammatory activation of neurons and
microglial cells in the posterior horn of the spinal cord occurs under conditions of
sustained nociceptive input. Counter-regulatory action upregulates the expression of
cannabinoid receptors CBR1 and CBR2 and enhances the activity of EC enzymes. If the
system fails to control the pronociceptive and inflammatory processes, the net
result is a decrease in EC-tone, increase of glutamatergic transmission of sensory
neurons and inflammatory activity of microglial cells, and reduced activity of the
endogenous pain control system [24].
An immunohistochemical study of peritoneal tissue from 45 patients with endometriosis
and chronic acyclical pain showed signs of peripheral sensitization, in which
transient receptor potential vanilloid-1 (TRPV1) channels, among others, were
increased in expression in sensory neurons compared to control samples [25]. Since the cloning of TRPV1, at least five
additional TRP channels have been discovered in dorsal root ganglia, which are also
found in primary somatosensory neurons [26].
These channels are considered sensory transducers that may be involved in the
generation of pain sensations evoked by thermal, mechanical, or chemical stimuli.
Six of these channels can be modulated by various endogenous, phytogenic, and
synthetic cannabinoids [26]. These six
channels, TRPV1-TRPV4, TRPA1, and TRP melastatin-8 (TRPM8), are also referred to as
ionotropic cannabinoid receptors [26]. For
example, the EC anandamide (AEA) shows characteristics of a TRPV1 agonist [27], at least at high concentrations [28]. N-arachidonyl dopamine and AEA were
identified as the first endogenous antagonists of TRPM8 [29]. Delta-9-tetrahydrocannabinol (THC) acts
most strongly on TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, but
does not appear to interact with TRPV1 [30].
Cannabidiol (CBD) appears to act more through indirect enhancement of EC tone and
direct anti-inflammatory effects [30]. CBD has
a low affinity for CBR1- and CBR2 but is most effective at TRPV1 and TRPM8 channels
[30].
Exposure to different contexts influences pain perception and therapeutic outcome by
activating specific neurobiological mechanisms, which have been studied in detail
using placebo and nocebo effects as models [31]
[32]. A positive and rewarding
context can bring about pain relief. An important neurobiological mechanism for this
is the activation of the endogenous pain control system, which is primarily based on
the endorphin and EC systems. [31]
[32]. There are individual differences in the
weighting of the respective systems [32],
which may also be the result of pharmacological conditioning. If opioids were
primarily used for pain relief in the past, the endorphin system might predominate;
if cyclooxygenase inhibitors (e. g., ibuprofen) or acetaminophen were
primarily used, the ECS is predominant [32].
Both cyclooxygenase inhibitors and paracetamol can increase the tone in the ECS via
manipulation of the elimination system of EC (fatty acid amide hydrolase [FAAH] and
fatty acid binding protein [FABP]) [33].
In addition, the ECS is also involved in memory extinction (long-term depression,
LTD) [34], e. g., by modulating
GABAergic transmission in the basolateral amygdala [35] or by suppressing the activity of supraspinal nociceptive networks in
the presence of enhanced CB1 activity in the periaqueductal gray [36].
The ECS is also associated with the endorphin system. For example, CBR1-knockout mice
showed an attenuated effect of opioid-dependent stress-induced analgesia [37]. Synergistic effects between cannabinoid
and opioid analgesia have been described [38].
Animal studies have been able to show that the combined intake of cannabinoids and
opioids was able to abolish the tolerance effects to opioids [39], and there is a significant opioid-sparing
effect under cannabinoid intake [40]. In a
cross-sectional study of individuals using medical cannabis, opioids,
benzodiazepines, migraine medications, and sleeping pills, in particular, were found
to be reduced [41].
Chronic pain, chronic stress, and the endocannabinoid system
Chronic pain, chronic stress, and the endocannabinoid system
Pain is a complex phenomenon for which mere sensory perceptions and the emotional
experiences are significant [12]. Pain and
stress are closely linked on several physiological and psychological levels, and
this is especially true for chronic pain [10]
[12]. Both pain and stress are
influenced by psychosocial factors, including, for example, beliefs, life goals, and
fears [11]. The brain regions and networks
responsible for chronic pain processing and stress regulation show considerable
overlap. Most notably, these include areas in the amygdala, hippocampus, and medial
prefrontal cortex [11]. Chronic stress
increases the perception of pain, which has been discussed in the introduction.
Acute stress in chronic pain leads to an increase in pain. This process is also
known as stress-induced hyperalgesia (SIH) [42]. Recently, Löffler et al. (2023) demonstrated that in
patients with chronic musculoskeletal pain, even a cognitive stressor is sufficient
to induce SIH [43]. The brain areas involved
in pain and stress processing are densely packed with cannabinoid receptors [44]. Thus, the ECS appears critically involved
in cognitive and affective pain processing. This is supported by clinical as well as
experimental data, showing that cannabis-based medicines (CBMs) do not so much alter
pain intensity but rather the affective component of pain [45]
[46].
The ECS represents a buffer system of the central stress response [9]. In a yin-yang relationship, a reduction in
the concentration of AEA in the hippocampal and amygdala regions triggered by
stimulation of the FAAH activates the hypothalamic-pituitary-adrenocortical axis and
thus anxiety, storage of aversive memories and other fight-or-flight events. An
increase in 2-arachidonoylglycerol (2-AG) concentration, on the other hand, can
terminate this process. If this system collapses under a chronic stress condition,
the allostatic load can no longer be coped with and psychiatric comorbidities
(depression, anxiety disorder, post-traumatic stress disorder) may manifest [9]
[47]
[48]. There is a broad overlap
between these disorders and chronic pain [23].
Accordingly, experimental and clinical studies show that especially patients with
high central stress levels benefit from cannabinoid therapy. Functional magnetic
resonance imaging studies suggest that the limbic system, rather than the sensory
system, is addressed when 15 mg of THC is administered to volunteers in the
capsaicin model, consistent with the observation that participants perceived the
pain stimulus as less unpleasant, but pain intensity remained unchanged [49]. In a meta-analysis conducted on
experimentally induced pain, this finding was confirmed: while a significant
reduction in the pain affect was observed, there was no clear effect on pain
intensity [45]. One mechanistic study showed
that the more pronounced the dysfunctional cortico-mesolimbic connectome, the
greater the pain relief after sublingual administration of the average dose of
15.4±2.2 mg THC in patients with chronic lumbar ischialgia [50]. In patients with chronic pain due to
activated osteoarthritis, there were positive correlations in the change of ECS
markers and psychosocial symptom expression, such as anxiety and depression [51]. In patients with knee osteoarthritis who
were about to undergo knee replacement surgery, postoperative pain, and opioid
consumption were significantly increased in those who showed high 2-AG levels in CSF
and synovial fluid as an expression of a dysfunctional ECS [52]. A dysfunctional ECS has also been
demonstrated in patients with PTSD [53]. In
comparison to control groups, patients with PTSD showed decreased serum levels of
AEA and a compensatory increase in the concentration of CBR1 in the CNS in positron
emission tomography examinations [53].
Clinical evidence for cannabis-based medicines in chronic pain
Clinical evidence for cannabis-based medicines in chronic pain
Over the years, around 60 randomized controlled trials (RCTs) on the efficacy and
safety of CBM have been published. To better assess the results, roughly the same
number of systematic reviews and meta-analyses (SRMAs) were published from 2010
onwards [54]. This unfavorable ratio, combined
with very different statements ranging from clear evidence of efficacy to the
complete opposite, has not changed to this day [55]. The main problem with these SRMAs is that the RCTs studied are
notably heterogeneous in all respects, especially with regard to the specific CBM
used, the galenics, the pain situation, and the outcome parameters [54]. This is also reflected in the reported
Number Needed to Treat for Benefit’ figures, which show a high degree of
dispersion, ranging from 2 to 24 [56]. With
this in the background, many SRMAs conclude that the evidence is weak or
insufficient, and therefore such meta-analyses do not provide sufficient information
about what the best interventions are in terms of patient care [57]. In addition, the strong impression of
subjectivity that permeates supposedly objective quantitative methods often remains
[57]
[58]. For this reason, our research group deliberately avoided a
meta-analysis in an early systematic review to avoid misleading results based on the
data from these very heterogeneous clinical trials [59]. However, post-hoc analysis of the results of the clinical trials
reviewed revealed that apparently, those patients, in particular, benefited from
therapy with a CBM who had inadequate stress regulation [59]. Most SRMAs incorporated data from RCTs in
which nabiximols (THC and CBD in a 1:1 ratio) and dronabinol (THC) were
predominantly used [60]. When studies using
inhaled CBM were included, much more pronounced treatment effects were observed, at
least in the short term [61]. Previous
positive cannabis experiences of patients, which may affect conditioning in pain
relief, and pharmacokinetic factors could be the reasons for this. Another factor
limiting the validity of these studies is the issue of blinding. When cannabis
flowers are inhaled, blinding the study participants is more challenging than with
oral administration. In addition, when cannabis flowers are used, the entire
constituents (phytocannabinoids, terpenes, flavonoids) are most likely to influence
the effect profile, a process known as the “entourage effect” [62].
In an SRMA published in the British Medical Journal in 2021, Wang et al. [63] showed that the use of oral CBM for chronic
pain is associated with about a 20% chance of reducing pain
by+≥+30% and can also improve physical function and
sleep quality [63]. These effects were
observed regardless of the type of pain (neuropathic pain vs non-neuropathic pain,
tumor pain vs non-tumor pain) [63]. The
authors concluded that a trial of non-inhaled CBM can be attempted, particularly in
cases of failure of standard therapy [64]. In
a concomitant systematic review of mixed-methods studies on claims of patients using
CBM, oral preparations with a balanced ratio of THC to CBD or with high CBD content
were found to be preferred by patients [65]
[66]. In particular, women,
inexperienced users, or those who used cannabis only for medicinal purposes tended
to choose products with a low THC and high CBD content [66]. However, only 2.6% of the total
population of 1321 participants with chronic pain in this specific online survey in
the US reported that they had been advised by a physician, indicating a large
discrepancy between medical practice and cannabis product choice among respondents
[66].
An SRMA by Bialas et al. [67], which included
data from approximately 2500 patients, extends the knowledge of cannabis therapy
gained from RCTs by examining long-term observational studies of CBM (predominantly
used by inhalation). These showed highly significant improvements in pain intensity,
function, sleep quality, depression, anxiety, and overall quality of life. In
addition, approximately 16% of patients were able to discontinue their
opioid medication while receiving CBM therapy [67]. In contrast to nociplastic pain, there is no convincing evidence of
the efficacy of CBM in inflammatory pain at the clinical level to date [68]. On the other hand, there seems to be some
potential for the anti-inflammatory properties of cannabis constituents (especially
CBD, other phytocannabinoids, and terpenes) to be used clinically in the future for
certain conditions such as osteoarthritis or collagenosis [69].
Safety of cannabis-based medicines in chronic pain
Safety of cannabis-based medicines in chronic pain
Medications are judged not only by their efficacy but also by their risk of side
effects. An international group of pain therapists with and without experience in
the use of CBM, psychiatrists, neurologists, and scientists with expertise in the
pharmacology of cannabinoids, as well as representatives of a patient group (United
Patient Alliance), have shown by employing a decision analysis that CBM has a
greater significance in terms of improving quality of life compared to a reduction
in pain intensity alone [70]. This is
especially true when compared to duloxetine, gabapentinoids, and amitriptyline. With
additional consideration of the side effect profile, all three CBM (THC/CBD
1:1 combination, THC, CBD) showed an advantage over the above-mentioned
antidepressants and gabapentinoids [70].
In a recent meta-analysis that included an appreciable number of long-term studies,
Zeraatkar et al. [71] reported a prevalence of
adverse effects of about 26%. These are mostly mild and self-limiting side
effects such as dizziness, cognitive impairment, vomiting, drowsiness, impaired
attention, diarrhea, and nausea. Severe side effects such as syncope or hypotension,
adverse events leading to discontinuation of therapy, accidents and injuries, and
dependence and withdrawal symptoms are rare and occur overall
in+<+1 in 20 people treated [71]. With caveats to the overall limited evidence, other pharmacologic
treatments for chronic pain, such as gabapentinoids, antidepressants, and opioids,
has been suggested to be potentially associated with more (and more serious) adverse
events [71].
Cannabis hyperemesis syndrome (CHS), which overlaps with cyclic vomiting syndrome in
adults and whose occurrence appears to depend on the composition and quantity of
cannabis consumed, was first described in the 2000s [72]. The prevalence of CHS in recreational cannabis use was calculated at
0.01% – 0.05% in the Rome Foundation Global Study [73]. Data on the prevalence of CHS in medically
prescribed CBM are not available. Accordingly, the package insert for Sativex
Oromucosal Spray does not mention CHS as an undesirable side effect of this CBM
[74].
In a cross-sectional study in the database of the US Veterans Health Administration,
which investigated the influence of the introduction of medical cannabis laws on the
prevalence of cannabis use disorder (CUD), the prevalence of CUD increased by
0.135% in patients with chronic pain and by 0.037% without chronic
pain [75]. Neither the International
Classification of Diseases (ICD) of the World Health Organization nor the Diagnostic
and Statistical Manual of the American Psychiatric Association has developed the
definition of CUD specifically for the medical application of CBM in a clinical
setting [76]. To date, no specific measurement
tool exists to assess dependence or CUD when using CBM as a therapy [76]. In general, 10% of all people who
have ever used cannabis meet the criteria for lifelong cannabis dependence [77]. Nearly 50% to 60% of the
variance in CUD is associated with an addictive genetic effect [77]. Severe depression compared to no
depression may increase the risk of developing dependence on medical marijuana in
chronic pain patients, as shown in a regression analysis of 324 chronic pain
patients treated with medical marijuana [78].
Because cannabinoids are likely to have an opioid-sparing effect, the use of CBM may
reduce those risks posed by opioids (e. g., occurrence or exacerbation of
sleep apnea syndrome) [79]
[80]. However, only preclinical and
observational studies demonstrate the potential opioid-sparing effects of
cannabinoids in the context of pain management, as opposed to higher-quality RCTs
that did not provide evidence of opioid-sparing effects [81]. On the other hand, the uncontrolled
recreational use of cannabis is considered a risk for opioid abuse (“gateway
hypothesis”), for which Wilson et al. [82] presented an SRMA of six studies from the USA, Australia, and New
Zealand, in which they calculated an odds ratio (OR) of approx. 2.8 and 2.5 for the
use of opioids and the development of an opioid use disorder (OUD) with cannabis
use. However, they cautioned against the low quality of evidence with a moderate
risk of bias in their analysis [82].
Furthermore, only 6% of young adults start using cannabis before alcohol and
tobacco, as shown by the results of the Population Assessment of Tobacco and Health
study, which included data from 8062 young adults [83]. A prospective Dutch study showed that in light cannabis users,
cannabis intoxication does not affect implicit and explicit tobacco or cocaine
motivations [84]. In general, the transfer of
data from uncontrolled recreational cannabis use to the use of CBM in the context of
medical treatment is not readily transferable.
In children and adolescents who have an individual or familial predisposition to
schizophrenia and other psychoses, cannabis products containing THC may increase the
risk of psychosis [85]. Therefore, CBM should
not be used in this group, if possible, or with extreme caution. In general, the
indication should be strict in individuals aged+<+21 years.
This caution relates in particular to preclinical data suggesting neurodevelopmental
impairment from early and heavy cannabis use [86]. In humans, further in-depth studies are needed to determine whether
an earlier age of onset and a more intensive pattern of use play a causal role in
neurodevelopmental impairment and increase the risk of persistent, if not permanent,
adverse effects on mental health and cognition later in life [86]. Likewise, the indication should be
restrained in pregnant women, nursing mothers, and persons with severe
cardiovascular diseases.
In principle, smoking cannabis flowers can also lead to bronchial damage. The risk of
serious complications such as chronic obstructive pulmonary disease or bronchial
carcinoma seems to be lower than with smoking tobacco [87]. In general, a vaporizer should be used
when inhaling CBM. Vaporizing cannabis has been shown to reduce the risk of
respiratory disease compared to smoking, as it produces fewer or no unwanted toxic
pyrolytic compounds or by-products (e. g., carcinogenic polynuclear aromatic
hydrocarbons) and reduces exposure to carbon monoxide [88]. The epidemic of lung injuries associated
with the use of e-cigarettes or vaping products in various US states was primarily
associated with the use of cannabis-containing cigarettes [89]. However, the prevalence of cannabis vaping
at the state level was not positively associated with the prevalence of lung injury.
This indicates that the occurrence of these lung injuries may not simply be due to
the prevalence of cannabis vaping at the state level but rather the use of
contaminated or illegally acquired vapor products such as vitamin E acetate, which
are more likely in states with restrictive cannabis laws [88]
[89].
Differentiated sublingual formulations are currently under development to avoid
risks to the respiratory tract [90].
Practical Considerations
For CBM, the best balance between efficacy and risk of adverse events is usually
achieved in the low to moderate dose range [91]
[92]. For pharmacokinetic
considerations, oral preparations are often preferred as they have a longer-lasting
effect compared to inhaled cannabis [93],
which can be beneficial for persistent chronic pain. To improve oral
bioavailability, ingestion should occur after meals. The presence of high-fat food
has been shown to increase the time to peak plasma concentration and the area under
the curve of THC, implying increased mean absorption of THC compared to fasting
pharmacokinetic data, which could be due to the slowed transit time through the
gastrointestinal tract when fat is present [94]. However, since head-to-head studies are scarce, there is no clear
external evidence to date that cannabis flowers and oral CBM differ in terms of
efficacy, tolerability, and drug safety [95].
Ingestion via the lungs (with a vaporizer) or sublingually might have the advantage
that the highly psychoactive metabolite 11-OH-THC is formed to a lesser extent [93]
[96].
The much faster onset of action could have an advantage in the treatment of symptom
attacks [97].
Dosage should be based on the principle: start low, go slow, stay low. The initial
daily dose of cannabis flowers is 25–75 mg. For this purpose,
patients should use a precision scale. Dronabinol (THC) administration can be
started with 0.8 mg (1 drop) and oromucosal cannabis extract with
2.7 mg (1 spray). Nabilone is only available as a 1 mg capsule,
which is equivalent to the effect of approximately 7–8 mg of THC.
For oral forms of use, THC daily doses of a maximum of 30 to 40 mg (with CBD
addition) should usually not be exceeded [92]
[98]. There is much greater dose
variation in the daily dose of cannabis flowers due to the variable form of
ingestion and the different constituents; mean doses are usually less than
1 g per day, and in exceptional cases under the supervision of an
experienced medical cannabis clinician, 3 g per day should generally not be
exceeded. There is evidence from cohort studies and observation of everyday clinical
practice that the use of multiple constituents of the cannabis plant may have
advantages over single substances in terms of efficacy and tolerability. This could
be explained within the concept of polypharmacy in terms of, for example,
synergistic interactions and bioenhancement [99]. This approach fits with the general observation that in
pharmacological pain treatment, the combination of different agents is the rule
rather than the exception. In addition, many substances used for pain relief often
act through various mechanisms. One example is amitriptyline, which is used as a
multi-mechanistic agent for all types of chronic pain [100].
Challenges and cautions
Chronic pain is highly individual and dependent on genetic, epigenetic, and
biographical factors in terms of gene-environment interactions [101]. In this context, large interindividual
differences in the expression of the ECS are also found [102]. Avoidance behaviors, catastrophizing,
perseveration principles, or perfectionism are harmful coping strategies that can
increase pain. The inability to learn and use mindfulness-based practices or
relaxation techniques for oneself can be considered a barrier to pain control. All
of these factors contribute to the fact that the response to CBM can be completely
different for each individual.
After decades of cannabis outlawing and the associated lack of information and actual
treatment experience with CBM, expectations of CBM effects are very high, especially
with inadequate effects under standard chronic pain treatment. Expectations
significantly trigger the neurobiological mechanisms that produce placebo effects.
This may lead to an overestimation of the intrinsic effect of CBM and an
underestimation of the risks of cannabis use.
Another source of confusion is that the extent of the dysfunctional central networks
associated with more intense pain perception in patients with chronic pain treated
with CBM in clinical trials is generally unknown. Accordingly, findings such as that
CBM is most commonly used for osteoarthritis pain [103] may lead to unreliable conclusions, as it is not an
anti-inflammatory mechanism of CBM but an effect on the central stress and pain
processing networks responsible for symptom relief.
Finally, there are different weightings about what exactly patients benefit from when
taking CBM. In clinical trials in pain patients, pain intensity is usually chosen as
the primary outcome parameter. Pain patients, on the other hand, are often more
likely to benefit from CBM in terms of their overall quality of life [104]
[105], which can be understood as an indication of the pleiotropic effects of
CBM.
Conclusions
Chronic pain must be viewed holistically and can be considered as a disease in its
own right in cases of high emotional distress and functional impairment. The
pathophysiological correlate for this is a dysfunction of the cortico-mesolimbic
system. Clinical and experimental evidence suggests that CBM can exert positively
influence these maladaptive brain functions and thus contribute to a reduction in
symptom burden. Accordingly, there is moderate evidence that CBM can contribute to
significant improvements in pain, physical function, and sleep quality in some
patients with chronic pain while being well tolerated with only a low risk of severe
side effects, such as the development of dependence.
