Study Raises Questions About Use of Opioids by Cancer Patients

By Pat Anson, PNN Editor

A new study led by researchers in Australia is raising questions about the effectiveness of prescription opioids in treating cancer pain, saying the evidence from clinical trials is inconclusive or “largely lacking.”

Opioids are a common treatment for cancer pain and are often considered indispensable, particularly near the end of life or in palliative care when pain can be most severe. Virtually all medical guidelines – including the CDC’s – specifically exempt cancer patients from any recommended limits on opioids.

But the new study, published in A Cancer Journal for Clinicians, rejects that long-held medical practice, suggesting that opioids work no better than a placebo in relieving cancer pain and that non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin may be just as good or better.

The study examined findings from over 150 clinical trials involving opioids and cancer, and found that most were not blinded or placebo-controlled. That’s a recurring issue in pain research due to the ethical issues involved in giving patients an ineffective or non-existent analgesic, particularly if they have a terminal illness. Although that shortcoming is widely understood and accepted – the authors of this new study view it as lack of evidence.

“Opioids are the most commonly used treatments for cancer pain management, and, although we might have assumed that there were placebo-controlled trials to support this widespread practice, our findings highlight that the evidence is largely lacking,” wrote lead author Christina Abdel Shaheed, PhD, Senior Academic Fellow at the University of Sydney School of Public Health, Faculty of Medicine and Health.

“There was an absence or paucity of placebo-controlled trials for some of the most commonly used opioid analgesics for cancer pain, including morphine, methadone, buprenorphine, fentanyl, hydromorphone, oxycodone, and tramadol.”

Ironically, Shaheed and her co-authors found that “weaker” opioids such as tapentadol and codeine may work better for cancer pain than the more potent opioids.

They also suggest that NSAIDs and antidepressants are more effective and have fewer side effects for someone with “background” cancer pain who is not nearing the end of life. In effect, they’re saying that opioids are only good if you’re dying.

“In practice, opioids are indispensable for intractable pain and distress at the end of life. What is worth highlighting is that non-opioids, particularly NSAIDs, are surprisingly effective for some cancer pain, and may avoid the problems of dependence and waning opioid analgesia over time,” said co-author Jane Ballantyne, MD, a retired anesthesiologist and professor at the University of Washington.

Ballantyne is Vice President of Clinical Affairs for Physicians for Responsible Opioid Prescribing (PROP), an anti-opioid activist group that advised the CDC during the drafting of its controversial 2016 opioid guideline. Like several other PROP members, Ballantyne has worked as a paid expert witness for law firms involved in opioid litigation.

This is not the first time Ballantyne has said that opioids should be used more cautiously when cancer patients are not terminally ill. In 2007, she wrote an op/ed saying that cancer treatment and survival rates had improved so much that opioids should no longer be viewed as the go-to treatment for cancer pain.  

“Cancer was once an explosive, typically terminal disease and became the prototype for end-of-life opioid pain treatment. However, cancer is no longer such an explosive disease, and many cancer sufferers can now expect to have a prolonged, even normal, lifespan. They may need pain treatment, but this treatment should not be modeled on palliative care paradigms,” Ballantyne wrote.

Many cancer patients are already struggling to get pain relief. A recent study found the number of cancer patients seeking treatment for pain in U.S. emergency departments has doubled in recent years. Nearly half of those ER visits were deemed preventable -- meaning they could have been avoided if the patient has received proper pain care earlier.

Other studies have documented how opioid prescriptions and doses have declined significantly for U.S. cancer patients. The Cancer Action Network warned there has been “a significant increase in cancer patients and survivors being unable to access their opioid prescriptions.” 

Are you a pain patient who has trouble getting your opioid prescriptions filled? There’s still time to take PNN’s survey on how opioid shortages are affecting patients at pharmacies. Click here to take the survey, which should only take a few minutes.

How Chronic Pain Disrupts Emotions

By Pat Anson, PNN Editor

Does waking up with pain everyday put you in a bad mood? Do you lose your temper easily or worry a lot?

It could be a sign that chronic pain has created a chemical imbalance in your brain that makes it harder for you to keep negative emotions in check, according to a new study by Australian researchers.

“Chronic pain is more than an awful sensation,” says senior author Sylvia Gustin, PhD, a neuroscientist and associate professor at the University of Sydney’s School of Psychology. “It can affect our feelings, beliefs and the way we are. 

“We have discovered, for the first time, that ongoing pain is associated with a decrease in GABA, an inhibitive neurotransmitter in the medial prefrontal cortex. In other words, there's an actual pathological change going on.”

Gustin and her colleagues at Neuroscience Research Australia (NeuRA) used advanced neurological imaging to scan the brains of 48 people. Half of them lived with a chronic pain condition, while the other half had no history of chronic pain and served as a control group.

Their findings, recently published in the European Journal of Pain, showed that participants with chronic pain had significantly lower levels of GABA than the control group – a pattern that was consistent regardless of the type of chronic pain. 

Neurotransmitters help communicate and balance messages between cells in the brain and central nervous system. While some amplify signals (excitatory neurotransmitters), others weaken them (inhibitive neurotransmitters). GABA, or γ-aminobutyric acid, is one of the latter. It acts in the brain as emotional regulator that helps dial down our emotions.

“A decrease in GABA means that the brain cells can no longer communicate to each other properly,” Gustin explained in a news release. “When there’s a decrease in this neurotransmitter, our actions, emotions and thoughts get amplified.”

While the link between chronic pain and decreased levels of GABA has previously been found in animals, this is the first time it’s been demonstrated in humans. Gustin hopes the findings will encourage people with chronic pain who may be experiencing mental health issues. 

“It's important to remember it’s not you – there’s actually something physically happening to your brain,” she says. “We don't know why it happens yet, but we are working on finding solutions on how to change it.”

GABA is not the only neurotransmitter that’s impacted by chronic pain. In a previous study, Gustin and her research team found that levels of glutamate, the main excitatory neurotransmitter, are also lower than average in people with chronic pain. Low glutamate levels are linked to increased feelings of fear, worry and negative thinking.

“Together, our studies show there's really a disruption in how the brain cells are talking to each other,” says Gustin. “As a result of this disruption, a person’s ability to feel positive emotions, such as happiness, motivation and confidence may be taken away – and they can’t easily be restored.” 

Medication can help relieve chronic pain, but there are currently no drugs that directly target GABA and glutamate levels in the brain. Gustin and her team are developing an online emotional recovery program as a non-pharmaceutical option for treating neurotransmitter disruption. 

“The online therapy program teaches people skills to help self-regulate their negative emotions,” says Gustin. “The brain can't dampen down these feelings on its own, but it is plastic – and we can learn to change it.”

Study Finds Little Evidence to Support Use of Acetaminophen

By Pat Anson, PNN Editor

Acetaminophen is the most widely used over-the-counter pain reliever in the world — the active ingredient in Tylenol, Excedrin, and hundreds of pain medications. The U.S. Centers for Disease Control and Prevention considers acetaminophen a “first-line” treatment for low back pain, osteoarthritis and migraine.

But a comprehensive review published in the Medical Journal of Australia found little or no evidence to support the use acetaminophen for most pain conditions. Researchers at the University of Sydney analyzed 36 studies involving over 19,000 people and concluded that the pain-relieving benefits of acetaminophen – known as paracetamol outside the U.S. -- are modest, at best.

“For most conditions, evidence regarding the effectiveness of paracetamol is insufficient for drawing firm conclusions. Evidence for its efficacy in four conditions was moderate to strong, and there is strong evidence that paracetamol is not effective for reducing acute low back pain,” wrote senior author Christopher Maher, PhD, a professor at the Sydney School of Public Health.

Maher and his colleagues looked at 44 pain conditions often treated with paracetamol, and could find only four for which there is high-quality evidence:

• Knee and hip osteoarthritis

• Tension headache

• Perineal pain after childbirth

• Craniotomy

Evidence for the other 40 pain conditions was low quality or inconclusive, including:

• Acute and chronic low back pain

• Major surgery

• Dental surgery

• Migraine

• Rheumatoid arthritis

• Hip fracture

• Cancer pain

• Neuropathic pain

“While paracetamol is widely used, its efficacy in relieving pain has been established for only a handful of conditions, and its benefits are often modest. Although some trials have evaluated regimens that may have underestimated its utility, the clinical application of paracetamol is primarily guided by low quality evidence, at best,” researchers said.  

A 2015 study in the British Medical Journal also found that paracetamol was ineffective for low back pain and provided little benefit to people with osteoarthritis.

In recent years, some U.S. hospitals have started using paracetamol as an alternative to opioids for post-operative pain, a practice not supported by the Australian study.

One limitation of the University of Sydney review is that most of the studies that were evaluated only used a single dose of paracetamol, which does not reflect its typical use.  Perhaps for that reason, researchers found that adverse events were similar for patients receiving paracetamol or a placebo.

Over 50 million Americans use paracetamol (acetaminophen) each week to treat pain and fever. Long-term use has long been associated with liver, kidney, heart and blood pressure problems. Acetaminophen overdoses are involved in about 500 deaths and over 50,000 emergency room visits in the U.S. annually.