Pain is one of the top and most quality-disrupting symptoms associated with cancer and cancer treatment. Pain is a common component of treatment for cancer, but pain often lingers long after treatment is complete. A 2023 meta-analysis of 444 studies provided updated 1 clarity on the prevalence of pain in patients with cancer: 44.5% of all patients experienced pain, with moderate to severe pain at 30.6%.
A dominant number of patients with cancer are either prescribed opiates or regularly take opiates. The differentiation factor between prescribed and regularly take is important because the former does not 100% equate to the latter. A 2024 study of the veteran population found that 70% of individuals with cancer were prescribed at least one opiate compared to 36.7% of those individuals without cancer. Before to the pandemic, the prevalence of opioid dispensing 2 claims in U.S. cancer patients decreased from 40.2% to 34.5%. The reported opioid use 3 among recent cancer survivors was 54.3% according to a 2020 study.
Misuse of opioids is a highly publicized national problem in non-cancer individuals. Could misuse of opioids also apply to cancer patients? The short answer is yes. A 2024 article published in the British Journal of Cancer found the prevalence of opioid misuse in cancer patients ranged from 5.7% to as much as 84%.
The most prominent prescription medication used to target cancer-related pain is the broad class of opiates. Many of these commonly prescribed opiates have immunosuppressive activity and should be avoided in combination with immune-stimulating therapies.
Why is immunosuppression a concern? Immune evasion by cancer is a rate-limiting step in cancer metastasis. Remember, 90% of morbidity and mortality is associated with cancer metastasis. When cancer can evade the immune system, the body’s defense, it can wreak havoc throughout the body. Cancer is fully able to do this on its own. Adding therapies that expedite immune suppression and evasion is a double whammy not needed. Below, you will see that opiates reduce the efficacy of immunotherapy.
Below are the top prescribed opiates and their impact on immune activity.
Morphine
Morphine has strong immunosuppressive effects. Morphine inhibits both innate and adaptive immunity. Moreover, it modifies the synthesis of cytokines, reduces the activity of natural killer (NK) cells, and decreases the proliferation of cytotoxic T cells. Clinical research connects the use of morphine and an increased risk of infection in cancer patients. Morphine should be avoided.
Fentanyl
Fentanyl equally has strong immunosuppressive effects. Fentanyl significantly inhibits the natural killer cell function, impairing immunosurveillance. Fentanyl’s immunosuppressive effect is similar to that of morphine. Fentanyl should be avoided.
Methadone
Methadone has moderate immunosuppressive effects. There is evidence that methadone suppresses cytokine production in in vitro studies. Though not in human studies, preclinical studies suggest methadone has immunosuppressive effects. Compared to Morphine, Fentanyl, and Codeine, there is a lack of clinical data currently available. Methadone should be avoided if possible.
Oxycodone
Oxycodone has immunosuppressive effects that range from mild to moderate. Oxycodone, in comparison to morphine, is shown to have less immunosuppressive effects. Compared to morphine, the immunosuppression by oxycodone is for a shorter time period. Compared to patients with increased infection risk associated with morphine use, oxycodone is associated with decreased infection risk. Oxycodone should be avoided if possible.
Hydromorphone
Minimal research has been published on the immunosuppressive effects associated with hydromorphone. Hydromorphone has not been shown to have any substantial impact on immune cell activity, which indicates a low immunosuppressive impact.
Hydrocodone
According to preclinical studies, hydrocodone has minimal immunosuppressive effects and only a minor impact on immunological function. It would be best to avoid hydrocodone if possible.
Buprenorphine
Buprenorphine has shown very little to no immunosuppressive effect. In contrast to immunosuppression, buprenorphine has a neutral to positive immunological profile, no inhibition of natural killer (NK) cell function, or no significant cytokine disruption compared to the opiates described above. Please discuss the option of buprenorphine use for pain management with your Williams Cancer Institute team.
Tramadol
Tramadol is an opiate that improves immune function and increases natural killer (NK) cell activity. In animal models, it has been shown to decrease the rate of tumor metastasis. Please discuss the option of buprenorphine use for pain management with your Williams Cancer Institute team.
Let me get a little more granular. What if opiates did more than suppress the immune system? What if opioid use suppressed immune checkpoint (ICI) immunotherapy? For example, the most negatively implicative immunosuppressive opiate, morphine, suppresses CD8+ T cell activity. This suppressed CD8+ T cell activity reduces the effectiveness of the anti-PD1 ICI immunotherapy. A mouse model of oral morphine in combination with immunotherapy showed a significant decrease in anti-PD1 immunotherapy efficacy, larger tumor size, and a reduction in survival .
It has been repeated that immunotherapies, as a whole, are limited in their efficacy. Published estimates of direct immunotherapy efficacy show a positive response in only 15-25% of cases. Of course, this is via systemic delivery. This low immune response is primarily due to “cold”, non-immunogenic tumors. “Cold” tumors are tumors that express:
•Low PD-L1 expression
•Low tumor mutational burden (TMB)
•Minimal or excluded CD8+ T cell infiltration
•Immunosuppressive cytokine profiles (TGF-β, IL-10)
•Dense extracellular matrix (ECM) and fibroblast activation
•High levels of regulatory cells, i.e., Tregs, M2 macrophages, N2 macrophages and
MDSCs
Many therapies are utilized to turn cold tumors “hot” to move a non-immunogenic responsive tumor to an immuno-responsive tumor. Therapies like PEF, hyperthermia, and ivermectin have been shown to turn cold tumors hot. When you look at many of the protocols in oncology, i.e., corticosteroids, Tylenol, and opioids, it appears that the push is to do just the opposite: turn hot tumors cold through protocols with immunosuppressive medications.
If you have been recommended or prescribed opiates by another physician, please be informed and notify your team of the research regarding the profound immunosuppression, and in particular, if you are on immunotherapy, as there may be viable non-immunosuppressive alternatives.
To connect with Dr. Nathan Goodyear and learn more about integrative cancer care, click here.
References
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