Introduction

Although cancer does not always mean you will have pain, cancer pain is one of the most common features across a wide range of cancer types, this does not refer to pain caused by tumours specifically, but also includes pain associated with cancer treatments such as surgery, chemotherapy, radiation therapy, targeted therapy and vice versa.¹ For example, peripheral neuropathy is a type of pain caused by chemotherapy. Pain caused by cancer itself can be split into 2 categories: chronic and acute.

Chronic pain

Chronic pain lasts for a long period of time, cancer pain can be considered chronic if it lasts for 3 months or more and can vary from mild to severe. It is usually caused by alterations in the nerves due to either tumour suppression or due to cancer treatments; chemicals released by the tumour can also lead to pain.² 

Acute pain

Acute pain is usually severe and characterised by its sudden onset and short-lasting period. This can be a response to tissue injury as the tumour grows, and will diminish with tissue healing. However, if managed improperly, it can develop into chronic pain.²

Comprehensive pain assessments can be performed to determine the intensity of pain, for example, patients may be asked to rate their pain on the Numerical Rating Scale of 0 to 10, in some cases there are patients who are unable to exhibit behaviour response to pain or provide a valid pain history, it depends on the judgement of the clinicians to consider whether pain is expected from other patients with similar disease burden and monitor for response, after which a management plan can be constructed.³

Drugs can be prescribed by doctors to relieve pain. The World Health Organisation (WHO) has provided a framework for pain management, named the WHO Analgesic Ladder, giving a stepwise approach to treat pain depending on its severity. Step 1 of the ladder refers to the mildest pain, where over-the-counter drugs are recommended, such as non-opioid drugs like paracetamol, or non-steroidal anti-inflammatory drugs (NSAIDS). Step 2 weak opioids can be used in addition to non-opioids and NSAIDS to relieve mild to moderate level of pain, for example codeine and dihydrocodeine; Step 3 refers to severe pain, where strong opioids such as morphine, diamorphine or fentanyl can be used in combination with non-opoids plus NSAIDS; and for Step 4, non-pharmacological management options for pain can be considered.⁴ Although this ladder has been undergoing debates of whether it remains optimal for treating pain in all patients, it has been approved to be effective in treating cancer pain in the majority of patients.

Opioids for cancer pain relief

Opioid is a common type of analgesic that is often used in managing cancer pain, as listed in the WHO Analgesic Ladder. It can take multiple forms and can be administered in various ways. Among the different forms, they are categorised into short-acting and long-acting opioids, the long-acting opioids take longer to work but can provide ongoing relief and only needs to be taken once to twice per day; whereas short-acting forms are immediate release (IR) opioids that have a quicker onset, making these more suitable to treat acute pain, but they don’t provide relief for long thus might need to be taken several times a day.⁵ There are also cases where the same opioid is used to treat chronic and acute pain at the same time for better pain control. 

Mechanism of action

Opioids express their pain-relieving effect through interaction with opioid receptors naturally existing in our body. There are multiple receptors for opioids to work on, including µ (mu; MOP) receptor, δ (delta; DOP) and κ (kappa; KOP) opioid receptors, along with other non-classical receptors for nociceptin/orphanin FQ (N/OFQ) or NOP. All the classic opioid receptors are G-protein coupled receptors, which means these receptors couple via the inhibitory G protein (Gi); the binding of opioids facilitates G protein interaction. This interaction allows opioids to modulate both afferent and efferent parts of the pain pathway by reducing release of the neurotransmitters, thus preventing pain transmission from the primary afferent neurons to the second-order ascending neurons, as well as second to third-order transmission, enhancing inhibitory control activity.⁶

Limitations

Although opioids are essential for medical use, there are several noticeable limitations to consider in order to administer drugs safely. Other than the pain relief effects, opioids are also known for their addictive properties; therefore, it is important to look out for any signs of developing opioid tolerance and addiction, as well as opioid overdose. If opioids are taken regularly for a long period, a larger dose will be needed to achieve the same relief effect as before, this is not because the pain has increased but your body getting used to having opioids, if you try to put a sudden stop to administration, withdrawal symptoms are likely to occur. These symptoms can be physical and psychological, including anxiety, depression, diarrhoea, insomnia and craving. Other than risks of addiction, there are also side effects that accompany standard usage of opioids, which vary from person to person, such as constipation, nausea and vomiting.⁵

Medical cannabis for cancer pain relief

Cannabis, also commonly known as marijuana or weed, is a plant consisting of several chemicals called cannabinoids, with the major compound being Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the substance giving psychoactive effects on the brain, whereas CBD is shown to have a pain-relieving effect as well as decreasing inflammation and anxiety in the absence of the high effect of THC.⁷

Similar to the mode of action of opioids, cannabis also has its receptors to bind to called endocannabinoid receptors (CB1 and CB2), and performs pain modulation by decreasing neurotransmitter release and activating descending inhibitory pain pathways. Cannabis’s medicinal use and recreational products from it has been explored for hundreds of years and there are lots of investigations into the potential of cannabis-based products as cancer treatment, however the scientific research on this still remains in laboratories with mixed results, it is still not valid whether cannabis can be approved to treat cancer, furthermore cannabis is a class B drug in the UK which means it is illegal to possess or supply cannabis.⁸ However, there are cannabis-based products that can be applied to multiple medical conditions to relieve symptoms, which can only be prescribed by specialist doctors. For example, Nabilone, a drug developed from cannabis licensed for treating severe sickness from chemotherapy.⁹ 

Does cannabis actually possess cancer pain relief properties?

Several studies have investigated the pain relief role of cannabis specifically on cancer pain, with varying conclusions. One study collected data from cancer patients who were part of the Quebec Cannabis Registry, including Brief Pain Inventory (BPI), revised Edmonton Symptom Assessment System (ESAS-r) questionnaires, total medication burden (TMB) and morphine equivalent daily dose (MEDD), recorded at 3-month, 6-month, 9-month and 12-month. Statistically significant decreases in BPI and ESAS-r pain scores can be observed at 3, 6 and 9 months, while decreases in TMB can be observed across all time periods. Out of the 358 patients, only 11 reported adverse effects, of which the 2 serious events (pneumonia and cardiovascular event) are unlikely to be related to cannabis usage.¹⁰ 

Whilst this study demonstrates the efficacy and safety of cannabis, other studies have proved otherwise. Several studies focused on assessing the efficacy of a mouth spray with a combination of THC and CBD against a placebo, and in general, the outcome of the therapy was no better than placebo in relieving pain in cancer patients experiencing moderate to severe pain despite opioid treatment. There was no difference in serious adverse effects between the mouth spray and the placebo.¹¹

Can medical cannabis replace opioids?

Whilst the usage of opioids has already developed into a mature operation as a choice to treat cancer pain, medical cannabis is still at the stage of clinical investigations with several uncertainties. The current main goal is to continue to explore the potential of cannabis-based products to support analgesic effects of medications, as opioids cannot provide pain relief in 100% patients, there are approximately 30% to 50% of cancer patients who will experience moderate to severe pain, among them 10% to 15% of patients reported that pain relief provided by opioids or combination of medication with NSAIDS are insufficient, calling the need for new analgesics to fill in the gap, in addition to another concern of opioid’s potential for abuse and developing dependence.¹¹

The are multiple major issues with cannabis, for example, the significant restrictions placed on cannabis due to its psychotropic effect, along with prohibition of cultivation and production, which add difficulties in conducting comprehensive research on its potential medical use;¹² just like usage of opioid can develop opioid use disorder, cannabis use disorder (CUD) exists as a mental health disorder associated with problematic patterns of cannabis use, cannabis addiction is the more severe form of CUD, including cravings, tolerance, and withdrawal symptoms which can heavily impair your life quality, and vice versa.¹³ 

Despite the strong evidence supporting that cannabis can be used as a standard analgesic for treating cancer pain is still lacking, there are cases that indicate cannabis’s success in reducing opioid dosage in patients experiencing non-cancer pain, as well as substituting for opioids to achieve therapeutic effects. This highlights the clinical significance of cannabis, as well as the use of both modalities in combination instead of focusing on a single treatment approach. 

Conclusion

Up to date, opioids remain the preferred therapeutic approach to treat cancer-related pain, however, their potential side effects and their insufficiency in a noticeable proportion of patients indicate the importance of analgesic innovations. Meanwhile, there is limited data available to demonstrate the efficacy of cannabis-based products in treating pain and whether it is safe enough to act as a substitute for opioids. Furthermore, the determination of cannabis efficacy remains difficult due to the high variability of cannabis-based products, for example, different administration routes, varying ratios of THC: CBD and vice versa. Accumulating cases of patients choosing to use cannabis as pain relief emphasise the potential of cannabis and cannabinoids; however, there is still limited data available from convincing clinical trials to demonstrate the efficacy of cannabis-based products in treating pain and whether it is safe enough to act as a substitute for opioids.¹⁴ Further clinical trials are required to investigate their clinical safety and efficacy, taking interaction of cannabinoids with other drugs, including opioids and NSAIDS into account in order to set up more sufficient combination therapies for cancer-related pain relief.