Opioids, Cancer Pain, and Maybe a Side Order of Corruption

“The world’s largest review on opioid medicines for cancer pain has found it is unclear whether some commonly used opioid medicines are better than a placebo and suggests that nonopioid medicines, including aspirin, may be as effective as opioids.” 

The quote comes from the study’s associated press release. But reading the 19-page research reported in Cancer reveals a different story. The questions, in bold, are mine; the answers come directly from the meta-analysis of 150 publications looking at treating chronic pain associated with a cancer diagnosis.

What type of pain are we talking about?

Specifically, the most common type of pain, nociceptive pain – caused by sensory nerve endings, nociceptors, that respond to potentially harmful stimuli. [1] Opioids bind to opioid receptors and modulate the response of nociceptors both presynaptically, inhibiting the release of neurotransmitters, and post-synaptically, blocking and reducing the transmission of nociceptive signals.

Are there “standard” protocols for managing chronic pain associated with cancer?

As a generalization, pain management in treating chronic pain involves a baseline or maintenance medication taken in regularized dosages and intervals, as well as “breakthrough” medications on those occasions when the maintenance medication is not sufficient [2]. The World Health Organization (WHO) and other national guidance often recommend a stepwise or “analgesic ladder” approach, beginning with nonopioid medications and progressing to opioids. The choice of initial medication and the pace of stepwise progression is based on

• The patient’s pain intensity
• The patient's response to therapy
• The potential for adverse effects, e.g., liver injury from acetaminophen or gastric discomfort from NSAIDs.

In general, appropriate pain management, like any chronic medical therapy, requires regular monitoring of treatment outcomes, in this case, reduction in pain intensity balanced against the development of adverse effects.

The American Society of Clinical Oncology “does not explicitly recommend morphine as first‐line treatment, arguing that the choice of opioid depends on pharmacokinetic factors, cost, tolerability, route of administration, and convenience to the patient.”

Are opioids effective in treating the pain associated with cancer?

In the words of the researchers,

“Opioid analgesics are the mainstay of management of moderate-to-severe cancer pain and are indicated for the treatment of cancer pain when nonopioid analgesics are insufficient or may be contraindicated.”

What about opioids compared to placebos? After all, a placebo generally has roughly 30% efficacy in treating many medical problems.

Opioids are more effective than placebos in reducing moderate-to-severe cancer pain because placebos have not demonstrated any significant efficacy. In studies that included mild-to-severe pain, tapentadol, and codeine, both opioids “may be more effective than placebo”; however, these studies were of low certainty.  Comparative studies of opioids have not indicated that one opioid is better than another in terms of efficacy or adverse effects.

A moment of editorial comment: does this response square with the initial statement that “it is unclear whether some commonly used opioid medicines are better than a placebo?” I think not. More questionable wordsmithing follows.

Can opioids be combined with nonopioid medications to improve pain relief and lessen opioid’s adverse effects?

“Although the opioid‐sparing effects of acetaminophen and NSAIDs have been well documented in the context of postoperative care and postoperative cancer care,… the opioid‐sparing effects of these medicines for background or breakthrough cancer pain remain largely unclear.”

• “The effect of acetaminophen [Tylenol] when added to opioid analgesics for cancer pain is inconclusive.”
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may “be similarly or more effective,” but “confirmatory evidence from robust clinical trials is warranted.”
• Antidepressants may be more effective than placebo and may improve opioid efficacy, but there is limited evidence comparing antidepressants directly to opioids for cancer pain. Limited evidence should result in limited conclusions.
• Anticonvulsants and Cannabinoids: “Overall, there is a paucity of evidence evaluating the[ir] use.”

Do opioids have adverse effects?

“Opioid analgesics can commonly result in opioid‐induced toxicities, including, but not limited to, gastrointestinal toxicities (nausea, acid reflux, loss of appetite, abdominal pain, bloating, and constipation) and central nervous system toxicities (somnolence, sedation).”

The predominant “toxicities” involve the GI tract and are primarily constipation. While acknowledging that constipation can negatively impact the quality of life, it is a tradeoff with a similar, if not more significant, reduction in the quality of life from cancer pain.

Let me pause again. There are any number of terms used to describe these adverse effects, the more neutral “side-effects” and the more damning “toxicities.” This is the only moment in the article where the implicit bias of at least one of the authors, Dr. Jane Ballantyne, a board-certified anesthesiologist at the University of Washington Medical Center, a retired member of the faculty, and “an early advocate for restraint in opioid prescribing for chronic pain” becomes clear. At the end of the analysis, the conflict of interest disclosures also note her work as an expert witness for two firms deeply involved in opioid litigation and “unpaid leadership roles in Physicians for Responsible Opioid Prescribing [PROP].” She is their Vice-President and routinely testifies to the “harm” of opioids. While the Vice-President role may well be unpaid, Dr. Ballantyne recognizes substantial income from payment as an expert witness.

What conclusions and considerations come from this meta-analysis?

“Opioid prescribing for cancer pain is a practice that, over centuries, has been considered necessary, but there are complexities in testing the efficacy of these medicines in the cancer setting…”

• Opioids are effective in managing cancer pain. Comparative trials have not indicated a preferred agent in terms of efficacy or toxicity profile.
• No medication was found to be superior to opioids in treating cancer pain.
• There is insufficient evidence to determine whether any adjunctive or substituted medication was superior to opioids in treating cancer pain. More robust clinical trials are needed to confirm their efficacy and compare them directly to opioids.

Once again, these conclusions are at variance with the earlier statement, “nonopioid medicines, including aspirin, may be as effective as opioids.” In their conclusion, the authors write, “The prevalence of opioid use disorder is approximately 24% in people with cancer‐related pain…” Here is what their cited source states, “The prevalence of opioid use disorder was 8% (1–20%)…” Is this an error, or is that implicit bias again rearing its misdirecting head? I suspect the latter. 

Any final thoughts?

What is worth highlighting is that nonopioids, particularly NSAIDs, are surprisingly effective for some cancer pain, and may avoid the problems of dependence and waning opioid analgesia over time.”

- Dr. Jane Ballantyne

“Some cancer pain” refers to mild-to-moderate pain. A meta-analysis of cancer related pain reported

“The treatment group with the lowest proportion of moderate to severe pain was the group after curative treatment (22.8%). Moderate to severe pain was most frequently reported in the group including patients without feasible anti-cancer treatment (43.3%).”

Personalized medicine requires treating the 43.3%, too. A one-size-fits-all prescription is a harmful fallacy.

The facts of the opioid crisis have never added up. This can be seen, in part, by noting a significant, unambiguous inverse correlation between US opioid overdose deaths (legal plus illicit) and opioid prescriptions beginning more than a decade ago. Yet, despite this obvious trend, PROP members, including Dr. Ballantyne, have continued to push for lower and lower prescribing, espousing the "evils" of opioid medications while at the same time working with law firms to enrich themselves as expert witnesses testifying in lawsuits against opioid manufacturers, distributors, and retailers. Given some of the bias and wordsmanship used in this paper, plus the fact that PROP members were intimately involved in the creation of the 2016 CDC Advice, where the war against narcotics officially began, it is perfectly reasonable to ask the question: "How much of the movement away from opioid drugs are financially motivated?"

[1] Stimuli include tissue damage, inflammation, and mechanical pressure

[2] Breakthrough pain is a “transient exacerbation of pain despite stable and adequately controlled background pain.”

Source: Opioid analgesics for nociceptive cancer pain: A comprehensive review Cancer DOI: 10.3322/caac.21823