New guidance aims to address confusion around the role of medical cannabis in the management of chronic pain

In The BMJ today, a panel of international experts make a weak recommendation for a trial of non-inhaled medical cannabis or cannabinoids (chemicals found in cannabis) for people living with chronic pain, if standard care is not sufficient.

The recommendation applies to adults and children living with all types of moderate to severe chronic pain. It does not apply to smoked or vaporised forms of cannabis, recreational cannabis, or patients receiving end-of-life care.

Their advice is part of The BMJ’s Rapid Recommendations initiative – to produce rapid and trustworthy guidelines for clinical practice based on new evidence to help doctors make better decisions with their patients.

Medical cannabis is increasingly used to manage chronic pain, particularly in jurisdictions that have enacted policies to reduce use of opioids. However, existing guideline recommendations are inconsistent, and cannabis remains illegal for therapeutic use in many countries.

Today’s recommendation is based on systematic reviews of 32 randomised trials exploring the benefits and harms of medical cannabis or cannabinoids for chronic pain, 39 observational studies exploring long-term harms, 17 studies of cannabis substitution for opioids, and 15 studies of patient values and preferences.

After thoroughly reviewing this evidence, the panel was confident that non-inhaled medical cannabis or cannabinoids result in small to very small improvements in self reported pain intensity, physical functioning, and sleep quality, and no improvement in emotional, role, or social functioning.

The panel found no evidence linking psychosis to the use of medical cannabis or cannabinoids, but say they do carry a small to modest risk of mostly self limited and transient harms, such as loss of concentration, vomiting, drowsiness, and dizziness.

The panel was less confident about whether use of medical cannabis or cannabinoids resulted in reduced use of opioids, and found that potential serious harms including cannabis dependence, falls, suicidal ideation or suicide were uncommon, but this evidence was only very low certainty.

The recommendation is weak because of the close balance between benefits and harms of medical cannabis for chronic pain. However, the panel issued strong support for shared decision making to ensure patients make choices that reflect their values and personal context.

And they suggest further research should explore uncertainties such as optimal dose and formulation of therapy, and benefits and harms of inhaled medical cannabis, which may alter this recommendation.

In a linked editorial, researchers welcome this new patient centred guidance, but say clinicians should emphasise the harms associated with vaping or smoking cannabis, discourage self medication, and pay particular attention to vulnerable populations.

“Increased pharmacovigilance of all cannabis use remains a priority, along with an ambitious programme of rigorous research on the short and long term effectiveness and safety of individual cannabis products for specific types of chronic pain,” they conclude.

Study finds that eicosapentaenoic acid, an omega-3 fatty acid, inhibits an important signaling molecule, thereby reducing chronic pain

A new study identifies vesicular nucleotide transporter as a novel target of eicosapentaenoic acid (EPA) and highlights the mechanism underlying the analgesic effect of EPA. EPA potently attenuates neuropathic and inflammatory pain and insulin resistance, with fewer side effects CREDIT Takaaki Miyaji from Okayama University

Eicosapentaenoic acid (EPA) is an essential nutrient belonging to the omega-3 group of polyunsaturated fatty acids (PUFAs). As the human body cannot synthesize PUFAs, dietary supplements containing EPA are required for normal physiological functions. Found abundantly in natural sources like fish, hemp oil, and linseed oil, EPA is known to exhibit anti-inflammatory, neuroprotective, and cardiovascular protective activities. Additionally, recent studies have demonstrated its therapeutic effects in reducing mortality risk after myocardial infarction, improving insulin resistance, reducing blood lipid levels, and inhibiting platelet aggregation. Omega-3 PUFAs have also been shown to decrease inflammatory responses following COVID-19 infection. Despite the wide spectrum of its therapeutic effects, the molecular target(s) and the underlying mechanism of EPA’s action remain elusive.

Research Professor Takaaki Miyaji from Okayama University, Japan, and his team of researchers have now uncovered a novel molecular target of EPA in their recent work published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) on July 18, 2022. Explaining the rationale behind their study, Research Professor Miyaji, the corresponding author of this paper, says, “Conventional molecular targets such as COX-2 inhibitors can explain the anti-inflammatory and analgesic effects for inflammatory pain, but not neuropathic pain, of EPA. However, since EPA significantly attenuates both inflammatory and neuropathic pain, there is a strong possibility that there exists another important molecular target of EPA related to neuropathy.”  Diving deeper, the team, thus, sought to understand the mechanism of action of EPA in alleviating both inflammatory and neuropathic pain.

During neurological, metabolic, and immunological disruptions, “purinergic” chemical transmission (a form of extracellular signaling mediated by purine derivatives), leads to the binding of energy carriers like adenosine triphosphate (ATP) to “purinoreceptors,” which induces and exacerbates neuropathic and inflammatory pain perception. This binding is mediated by a vesicular nucleotide transporter (VNUT), which thus becomes the key molecule in the initiation of purinergic signaling. The researchers hypothesized that EPA targets VNUT, thereby blocking purinergic chemical transmission and reducing pain perception.

Research Professor Miyaji and his team tested this hypothesis both in-vitro, using human derived VNUT, and in-vivo, using a VNUT-deficient mouse model.

They found that EPA competes with chlorine ions that normally activate VNUT and inhibits VNUT-mediated release of ATP. Moreover, they observed this effect with EPA and its metabolites only, and not with docosahexaenoic acid, another omega-3 fatty acid, thus, suggesting that the structure of omega-3 fatty acids with side chains is necessary for VNUT inhibition.  

Further, they induced neuropathic pain in wild-type and VNUT-deficient mice using chemotherapeutic agents that are used in cancer treatment. Notably, EPA accentuated pain in wild-type animals, but not in VNUT-deficient mice, thus corroborating their earlier finding on the inhibitory effect of EPA on VNUT. Similarly, insulin resistance induced by neuropathic pain has been shown to be reduced by EPA treatment in wild-type, but not in VNUT-deficient mice.

“We found that low concentrations of EPA completely and reversibly inhibited the release of ATP from neurons, without inhibiting the release of other neurotransmitters. Compared with other drugs, EPA demonstrated a higher analgesic effect and fewer side effects,” explains Research Professor Miyaji.

Besides, neuropathic pain and associated insulin resistance, the analgesic effects of EPA can be further extended to chronic pain associated with several other conditions like chemotherapy, diabetes, rheumatism, gout, sciatic nerve ligation, and inflammation. Additionally, purinergic chemical transmission is also associated with a variety of conditions including Alzheimer’s disease and depression, for which EPA can be explored as a therapeutic strategy.

Moreover, opioids and other pain-relief medications can have long-term side effects and result in addictions. In the absence of optimal drug treatments with fewer side effects, chronic pain leads to a decreased quality of life, besides increasing the economic burden of treatment. With this discovery, ‘nutrient-based EPA’ and its metabolites can be indicated in the management of chronic pain, while also keeping potential side effects at bay.

Elaborating the long-term implications of their research, Research Professor Miyaji adds, “Our results can help develop novel nutrient-based treatment and prevention strategies by targeting purinergic chemical transmission for inflammatory, neurological, and metabolic diseases, without the adverse side-effects of conventional pain-relieving medications.” 

Who wouldn’t be excited at the prospect of having safer and natural pain relief strategies? We certainly are!

Someone using an audio mixer. McCann London & Craft London,

A new study explores the use of music-listening to relieve acute pain, finding that people who were given the impression that they had control over the music they heard experienced more pain relief than people who were not given such control. Dr. Claire Howlin of Queen Mary University of London, U.K., and colleagues from University College Dublin, Ireland, present these findings in the open-access journal PLOS ONE on August 3, 2022.

Music listening can be used for pain relief, especially for chronic pain, i.e., pain lasting more than 12 weeks. However, the underlying mechanisms of these benefits are unclear, especially for acute pain, i.e., pain lasting less than 12 weeks. Basic musical features, such as tempo or energy, seem to be less important for pain relief; instead, feeling able to make decisions about the music may be key for pain relief. However, previous work has largely focused on findings from lab-based samples that did not explore real-world, pre-existing acute pain.

To improve understanding, Howlin and colleagues asked 286 adults experiencing real-world acute pain to rate their pain before and after listening to a music track. The track was specially composed in two different versions of varying complexity. Participants were randomly assigned to hear either the low- or high-complexity version, and some were randomly selected to be given the impression that they had some control over the musical qualities of the track, although they heard the same track regardless of their choice.

The researchers found that participants who felt they had control over the music experienced greater relief in the intensity of their pain than participants who were not given such an impression. In questionnaires, participants reported enjoying both versions of the track, but no links were found between music complexity and amount of pain relief. Additionally, participants who engage more actively with music in their everyday life experienced even greater pain-relief benefits from having a sense of control over the track used in this study.

These findings suggest that choice and engagement with music are important for optimizing its pain-relief potential. Future research could further explore the relationship between music choice and subsequent engagement, as well as strategies for boosting engagement to improve pain relief.

The authors add: “Now we know that the act of choosing music is an important part of the wellbeing benefits that we see from music listening. It’s likely that people listen more closely, or more carefully when they choose the music themselves.”