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NSAIDs v opioids: pain, repurposing and prescription in a crisis

by ecancer reporter Will Davies, reviewed by Dr Gabriel Rodrigues Martins de Freitas, University of Caxias do Sul

Pain is one of the earliest indicators of cancer, and chief among cancer patients’ fears.

Yet, it has so far escaped a widely accepted definition and breakdown.

Increasing pain as diseases progress can weigh on a patient’s physical ability, cognitive function and overall quality of life.

While relief of pain is an essential goal, many patients do not expect complete relief, and rate their pain control against their ability to go about leading a ‘normal life’.

Chronic pain (lasting over 3 months) afflicts up to half of cancer patients, with some reporting around 70% of head and neck cancer patients affected, and up to 90% of advanced lung cancer patients, whose severity of chronic cancer pain is even associated with shorter survival.

The standard scale for pain and response, the WHO pain ladder, was set out in 1986, and is reported at delivering effective pain management to anything between 100% and 20% of cancer patients.

The three-step ladder, which has been commonly transferred to non-cancer pain management, sets out brackets for severity of pain and the pharmacologic agents suitable to alleviate suffering, as best as is able.

  • Step 1 requires on NSAIDs and non-opioid medicines.
  • Step 2 matches increased pain with the inclusion of weak opioids
  • Finally on to strong opioids including morphine in Step 3 to treat severe pain.

The introduction of opioids up to, and including, morphine is intended to deliver quicker and more effective relief of cancer pain than NSAIDs, though superiority of any one opioid for controlling cancer pain specifically has not yet been established, and gaps in education may contribute to chronic under-treatment of cancer pain17.

The ladder itself has been subject to regular reviews and challenges, equally praised and criticised for its straightforward approach to pain management.

Of late, the prescription of opioids has come under closer scrutiny, in the wake of an ‘opioid crisis’ in the US and Europe.

In a UK context, out of the 16 million English and Welsh prescriptions for opioids, only 2 million are for cancer pain management.

Most of those prescriptions are for tramadol, which sits in the Step 2 bracket on the WHO ladder, among contentious company – discussion on the suitability of Step 2 opioids compared to low-dose regimens of morphine, which is equally effective, has yet to settle.

It is important to draw distinctions between patients who seek more opioid medication to better manage their pain, patients who intend to misuse their medication, and addicts:
‘Patients suffering unrelenting pain seek opioids or opioid dose escalation but they are not addicted. Patients who become opioid tolerant may suffer a re-emergence of pain or symptoms and seek more opioids, but they are not addicted. Patients who enter opioid pain treatment with a substance abuse disorder may display addictive behaviour, but it is not the pain treatment that made them addicted’

Patients at risk for opioid misuse are few, though the highest usage is reported by men aged 45-64 and some research indicates that cervical cancer patients are at the most risk.

Prescription of opioid analgesia for cancer patients, in general, has been linked to a mixed bag of subsequent survival advantages and hindrances, including lower overall survival and accelerated tumour growth on one side, with reduced angiogenesis on the other.

In the perioperative setting, opioid analgesia is linked to an uncertain array of positive and negative clinical outcomes.

Other preclinical trials have tentatively linked opioid agonists with cancer metastasis, immune suppression and growth factor expression, while retrospective studies show chronic opioid usage contributes to decreased survival in oral cavity cancer.

Tramadol, a synthetic opioid, binds m-opioid receptors and blocks reuptake of serotonin and norepinephrine .

Its use in place of morphine as analgesia for ovarian cancer surgery has been found to increase immune activity , and further mouse models showed fewer lung metastases.

Overall, long-term toxicity profile of combined NSAID and opioid regimens, as per Step 2 of the WHO schedule, remains uncertain, and there is a lack of evidence of efficacy for combined doses at higher levels.

The latest data demonstrates substantially higher opioid prescriptions for cancer survivors compared to those without a history of the disease, showing chronic cancer pain remains unresolved, leaving many patients at risk of either under-treatment or unmanaged dose reduction.

The go-to alternative for analgesia in Step 1 and 2 of the WHO ladder is non-steroidal anti-inflammatory drugs (NSAIDs), many of which are available without prescription at low cost.

Systematic reviews of NSAIDs with and without opioids for managing cancer pain have yet to reach consensus in regards to any one course being more effective at managing pain than another.

However, for treating non-cancer back pain, NSAIDS were found to be superior to mild opioids, which were in turn only slightly better than placebo and no better than paracetamol.

Being a widely available, cheap, moderately effective means of controlling cancer pain, combined with promising clinical and pre-clinical trials, has also led to wide drug repurposing efforts to understand and promote their tumour-limiting potential.

NSAIDs, including aspirin, have been described as near-globally chemo-preventive, and intraoperative use appears to improve outcomes for breast and lung cancer patients.

The mechanism behind this activity is unclear, though NSAID influence on cell adhesion and tumour cell invasion may be key.

Another indicated pathway is regulation of COX:  Inhibition leads to downregulated prostaglandin E2, in turn decreasing the risk of colorectal cancer by up to 25%, dependent on duration.

Ketorolac inhibits COX1 and, to a lesser extent, COX2, and has been linked to improved clinical outcomes – intraoperative use has been linked to improved disease free survival and overall survival among breast cancer patients.  

Most recently, perioperative use of COX-2 inhibitor anti-inflammatory etodolac has been found to reduce metastasis and disease recurrence, though low dose aspirin still has the most favourable profile of risk against balance for preventing relapsed colorectal neoplasia.

While this may seem to indicate NSAIDS a better choice for non-cancer pain, on top of their reported chemo-preventive properties, side effects including gastrointestinal bleeding, continue to complicate matters.

COX-2 NSAIDS were initially developed to reduce gastric side effects, but seemed to come at the risk of increased risk of heart attack and stroke, leading to the discontinuation of some drugs.

Ketorolac, prescribed to help manage cancer pain among others, and is known to increase the risk of gastric bleeds when administered with other NSAIDS.

The NSAID naproxen is associated with the lowest chance of cardiovascular side effects, but in turn comes with a dramatically higher chance of gastric bleeding and ulceration.

Long-term use of aspirin, among the most widely available NSAIDS, remains contentious, with longer regimens linked to increased risk of gastric bleeding and ulceration, though the full extent of pathways involved in this case remains unclear.

So where does this leave cancer patients on Step 2 of the cancer pain ladder, weighing the risks and benefits of opioids or NSAIDs, with pain the only certainty?

Prof Patrice Forget, of Vrije Universiteit Brussel (VUB), whose research looks at the impact of anaesthetic and analgesia on cancer survival, says “NSAIDs are a good alternative to weak opioids. But the NSAIDs can have limitations: Long term use and related side effects, short term side effects, or simply not sufficient effect to manage severe pain.  Severe pain can be managed with a medication combination, in opioid sparing strategies, when opioid free regimens are not possible. Ideally, the shortest and lowest doses could be recommended. But these doses and durations are difficult to define. Regarding the repurposing of these medications for their potential anticancer effect, one has to better understand the optimal candidates and timing before having clear recommendations.”

“Chronic pain management is a real challenge. Different strategies must be conjointly used. To limit the long term use of opioids and NSAIDs, specific antineuropathic medications may be useful. Non-pharmacological techniques are also recommended.”

“Opioids can be recommended for short term use, and after applying opioid sparing strategies, including appropriate non opioid medications. Long term routine use, especially with high doses, should be discouraged, limited to selected patients, as it is not clearly associated with any benefit but is well with side effects. These should be limited to on-demand intake, to promote activities and quality of life.” 

On the safety and utility of using NSAIDs to alleviate pain or control disease, Dr Farhat Khanim from the University of Birmingham, who works with the ECMC UK Therapeutic Cancer prevention network on chemoprevention and drug licencing, says

“It really has to come down to patient and individuality. Obviously we need to generate strong data about safety, and the risk ratio of every medication we wish to prescribe. But, that risk to benefit ratio will change based on your patient group.”

“If you are dealing with a relatively healthy group, for whom you are talking about prevention, then you want less risk, obviously. Therefore, considering the risk of GI bleeding with the use of NSAIDs compared to the addiction of opioids, the latter becomes a greater issue you have to consider more carefully.”

On the rate of gastric events with long term NSAID use, she said: “For an average risk individual aged 50 - 65, aspirin for 10 years reduced the relative cancer incidence and cardiovascular events by 7-9% over 15 yr period, with net 4% reduction in all deaths over 20 years. If we combine that with other types of screening as well, then we can increase the efficacy. The risk of bleeding is dose dependent, and we’re talking about low dose, so the risk is relatively low."

"The absolute risk is still relatively small. So I think what we need to consider is language as well, when we talk about increased risk; are we talking about 20%, or potentially from 0.5% to 2%. So we need to talk about relative risk and absolute risk.”

On the conflicting evidence of pro and anti-metastatic signalling from NSAID use, Dr Khanim said: “In most disease, inflammation has a role to play, and it’s fundamental; normal levels of inflammation are required signalling processes. However, what we know and understand is that excessive inflammation or uncontrolled inflammation can promote disease states. We accept that inflammation has a role to play in cancer and metastasis. I think what we need to do is think about how much we understand the process. More critically, what are the right drugs to reduce the risk of metastasis if we are going to target inflammation?”

As for the future of repurposes NSAIDs in cancer control, Dr Khanim adds: “We have to rethink the kind of clinical trials we want to do. If we look in the preventive setting, we have to look at thousands and thousands of patients. But they cost money and they take time. There’s data doming from he aspirin literature that says you only see results 10, 15 years down the line…”

“Ultimately, prevention is the best cure. Rather than getting to the point where we have to start treating, how can we prevent it getting there, or prevent it from spreading or coming back? What’s the most effective way? And that’s not just the context of a patient, but also the cost. We have to find effective, affordable solutions.”

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