By Roger Chriss, PNN Columnist

A standard critique of prescription opioids is the absence of good long-term data on safety and efficacy. Clinical trials are generally short-term and last only a few weeks, so questions about cumulative long-term risks, including addiction and overdose, remain unclear.

Clinical trials that run for a year or more are complex and costly. Attrition may be high and outcomes may be muddied by the inevitable effects of aging, disease progression, and life events. There are also ethical issues involved with subjecting patients to long-term trials where they may receive nothing more than a placebo.

In other words, launching new trials is often impractical. Fortunately, there are a few other ways to answer questions about long-term opioid risk.

Compare Outcomes

First, we can compare outcomes among patients whose key difference is opioid dosage. In a recent Canadian study, researchers looked at over 2 million individuals in Ontario given an opioid prescription between 2013 and 2016 for pain. They identified 1,121 patients who had a fatal or non-fatal overdose – a minuscule overdose rate of 0.0055 percent.

But when compared to patients getting relatively low daily doses of 20 morphine milligram equivalents (MME), those who received 200 MME or more had a “high hazard of overdose.”  

A dose of 200 MME may be an extreme example, since Canadian guidelines recommend that initial doses be limited to no more than 50 MME. But researchers said their study proves the value of guidelines. 

“Although the absolute risk of an opioid overdose within the first year of prescription opioid use is low, better alignment of opioid initiation practices with guidelines may reduce opioid-related harm,” they concluded. 

Compare Opioids 

Second, we can compare two opioids: oxycodone and hydrocodone. In a retrospective analysis of patients in Oregon between 2015 and 2017, researchers found that after an initial prescription in opioid-naive people, 0.3% experienced a fatal or non-fatal overdose and 2.8% refilled an opioid prescription at least six times, what the researchers considered “chronic opioid use.” 

Patients who received oxycodone were less likely to develop chronic use than those receiving hydrocodone, but the oxycodone patients had a slightly higher risk of overdose.  

Based on that finding, researchers concluded that “hydrocodone may be the favorable agent” when starting people on opioids. 

Compare Odds

We can also use statistical inference to estimate risks. In an analysis of 13,884 U.S. adults living with chronic pain between 1999 and 2004, epidemiologists found that 5% died from all causes within 3 years and 9% died within 5 years.  

Researchers found that chronic pain patients on opioids had a slightly higher risk of death – and calculated an odds ratio of 1.06 for them dying within three years and 1.03 at five years compared to those not taking opioids.  

It’s hard to infer much from a study like that, because researchers didn’t establish a causal relationship between opioids and death. Since chronic pain itself raises the risk of dying, the findings could simply mean that patients on opioids are sicker, in more pain, and closer to death.  

Despite this, researchers came to the sweeping conclusion that “chronic pain increased the risk of all-cause mortality through opioid prescriptions.” 

Compare Health Outcomes 

Last, we can look at health outcomes. An alarming, preliminary study from Taiwan evaluated chronic pain patients on long-term opioid therapy and found they have significantly higher risk for cancer compared to those not taking opioids. 

The overall hazard ratio for the opioid group was 2.66 – which means they have over twice the risk of having many different types of cancer. 

“Long-term opioid use might be a significant risk factor for breast, gastric, colorectal, ovarian, prostate, lung, pancreatic, head and neck, and esophageal cancers and HCC (hepatocellular carcinoma),” researchers concluded in their study, which has not yet been peer-reviewed. 

Risks of Other Drugs 

These findings help shed light on the long-term risks of prescription opioids, at least compared to healthy control subjects who do not take opioids. However, that is not the situation faced by most people with chronic illness, who are often on multiple medications to manage their pain and other symptoms.  

As a result, we need to know the risks of non-opioid pain management options. For instance, the consequences of cannabis addiction are low compared to opioids. But the cancer risk appears to be substantially higher. A major review in BMC Archives of Public Health found that “cannabinoids including THC and cannabidiol are important community carcinogens exceeding the effects of tobacco or alcohol.”

The risks of non-steroidal anti-inflammatory drugs (NSAIDs) are well-known. According to a 2011 review, “chronic NSAID use increases the risk of peptic ulcer disease, acute renal failure, and stroke/myocardial infarction. Moreover, chronic NSAID use can exacerbate a number of chronic diseases including heart failure and hypertension.” 

For other non-opioid medications, we lack long-term studies. For instance, a 2017 Cochrane review on gabapentin for chronic neuropathic pain notes that “study duration was typically four to 12 weeks.” Cochrane also notes that only short-term trials were conducted for serotonin and norepinephrine reuptake inhibitors like duloxetine for fibromyalgia.  

As for non-pharmacological options like spinal cord stimulators, the situation is similarly uncertain. A new Australian study in the Journal of Patient Safety found that for every 10 stimulators that were surgically implanted, four had to me removed for various reasons. That outcome went unnoticed in short-term studies and emphasizes the need for more careful patient selection and monitoring of outcomes.  

There are real risks to prescription opioids but it would be simplistic to dismiss them entirely. As pain physician Antje Barreveld notes in a recent STAT News op-ed: “Opioids do have a place in pain control and can be safely prescribed, even at high doses, by following best practices while monitoring for risks and side effects.” 

Understanding the long-term risks of prescription opioids will be important as the CDC finalizes its revised opioid guideline, and as regulators, insurers and clinicians decide how to act on them. But more generally, we need long-term studies of all pain management modalities so that we can better understand their risks.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.