Can pain relief help modulate the behavior of pets tumors?

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It's 2 a.m., and it wasn't a nightmare that disrupted Harvey's slumber-but nightmarish is exactly how you might describe what's about to unfold. His heart is racing. He feels cold and weak.

His constant panting and pacing has now awakened the rest of the family, who rush the 13-year-old golden retriever to the local emergency clinic. He's swept onto a gurney and taken to the back.

You notice Harvey's pale gums and distended abdomen. There's no history of trauma. No rat bait in the house. And it certainly wasn't the sight of Halloween ghouls that drained the all the blood from his face. Quick flash of the ultrasound and a 22-gauge needle, and you've got your answer: a bleeding splenic mass.

You take a deep breath and walk to the consultation room to let the family know that Harvey needs to be stabilized and taken to surgery right away. You explain the next steps: Several thousand dollars, a few days of postop recovery and a 70% chance of diagnosing a cancer-which will almost certainly take his life in just a few months, even with aggressive chemotherapy. Not great prospects. The family decides to move forward.

There's not much more we can do to optimize survival for dogs with visceral hemangiosarcoma beyond surgery and chemotherapy-perhaps an emerging immunotherapeutic. But imagine how empowered that overnight crew would have felt if they'd known that the drugs they used to anesthetize Harvey, along with the quality of nursing care provided to him, could have had just as much influence on his long-term prognosis as anything his oncologists could do in the coming weeks and months?

What's being done?

Research beginning in the 1990s found that opioid administration decreased various behavioral indicators of pain in rats that underwent abdominal surgery. That pain relief was accompanied by a significant decrease in lung metastasis.^1-3

This anti-metastatic drug effect was present and potent when the narcotic was administered before or after surgery. However, the effect size was largest when analgesia was provided preemptively. Thus, while surgery is essential to the management of various solid malignancies, these studies indicate that surgery-induced pain can promote tumor metastasis. This effect can be reduced with appropriate analgesia.

Anesthetic protocols can have similar influences on tumor behavior-for example, propofol exposure results in reduced migration of ER-positive and -negative breast cancer cells.⁴ Similar effects are seen in vivo.⁵

Though provocative, the aforementioned studies were performed in highly contrived laboratory models using a tail vein metastasis model. Essentially, tumor cells are injected intravenously; investigators then quantify retention of tumor cells in the lungs using radiolabeling or bioluminescence, or they quantify formation of metastatic foci with manual counting. This allows one to determine the impact of various interventions on lung metastasis. In the studies, the intervention was generally abdominal surgery plus or minus parenteral administration of either morphine or fentanyl. Such models are limited by their failure to recapitulate the entire multistep process of metastasis as would occur in a spontaneously occurring tumor.^6,7 Because of that limitation, it's fair to wonder whether or not these results might really have clinical significance.⁸

Transurethral resection is a cornerstone of treatment for people with non-muscle invasive bladder tumors (NMIBC), but recurrence is common. A recent retrospective study of 876 Korean patients indicated that the five-year tumor recurrence rate after resection was 53% when the procedure was performed under general anesthesia. That's significantly higher than the 42% recurrence rate for patients who had spinal anesthesia.9

On the contrary, a study comparing the effects of various analgesic protocols on local recurrence and overall survival after thoracotomy for resection of primary lung tumors in 1,729 people showed that patient-controlled analgesia and thoracic epidural analgesia was associated with higher hazard of dying as compared with paravertebral block. That effect was attributed to lower in-hospital mortality and higher survival in the early postoperative period. But there was no relationship between pain control method and cancer recurrence.¹⁰

The contradictory outcomes of these two studies represent just a small sample of the many studies that tackle this issue. And the overall story is similar-some studies show that analgesics and anesthetics impact tumor control and oncologic outcomes, and other studies show no effect. To date, there have been no large prospective clinical trials. But a Canadian research group recently independently published data that are in agreement with the aforementioned Korean study.¹¹ Both studies found that spinal anesthesia was associated with a lower risk of local tumor recurrence after resection for non-muscle invasive bladder cancer. This suggests that the phenomenon is real and that the discordance between various studies may reflect dependence of effect size on tumor biology (e.g., analgesia and anesthesia may impact tumor behavior for some types of cancer but not others). The type of drug, anesthetic or analgesic procedure may also have influence.

The exact means by which acute surgical pain potentiates aggressive tumor behavior is unknown. One proposed mechanism is pain-induced immunosuppression that allows migrating tumor cells to escape immune surveillance.^12-15 As mentioned, the provision of opioid analgesics in a rodent model reduced the tumor-promoting effects of surgery.¹⁵ Interestingly, though, morphine itself can also have tumor-promoting effects. And there is debate over whether opioids actually promote or prevent the spread of cancer.¹⁶

The next frontier

The interplay between surgical pain, analgesia and tumor behavior is incredibly complex. And adding to the complexity are potential (yet completely unexplored) complicating effects of uncomfortable side effects that may result from various adjunctive therapies (e.g., radiotherapy and chemotherapy).

There is a scarcity of research on this subject and a lot to learn. For certain, we don't yet have data for splenic hemangiosarcoma-so no recommendations for how to help Harvey. And in fact, we don't have these types of data for any kind of cancer in pets. But it's obvious we need to explore this possibility. And we need to do it now. America is facing an opioid epidemic, and as new non-narcotic analgesics are developed, we owe it to pets and people with cancer to develop strategies for managing acute and chronic pain that not only relieve pain, but also modulate tumor behavior in a manner that improves survivorship.

Dr. Nolan is an associate professor at North Carolina State University. He is principal investigator for several clinical trials aimed at developing novel cancer therapies; his laboratory focuses on reducing risk of severe cancer treatment-associated toxicity. Dr. Nolan also oversees the college's division of radiation oncology, including a world-class program in stereotactic radiotherapy. 

References

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