In this study, we found preliminary evidence for the importance of host genetic variability in cytokine genes on pain and analgesic response in patients receiving supportive care treatment. Specifically, we found that polymorphisms in TNF-308G/A
and IL6 −174G/C
may be important modulators of pain treatment and control. The magnitude of the association was most prominent with IL-6−174CC
genotypes, with carriers requiring more than 4× the MEDD relative to heterozygotes and wild-type carriers, even after adjusting for factors known to influence pain relief. The IL-6
gene is localized to chromosome 7p21. The IL-6 −174G/C
polymorphism affects transcription, altering serum levels of IL-6
, with the C allele associated with significantly lower levels of plasma IL-6 (24
). Our findings provide preliminary support for a role of IL-6
in pain severity by showing that patients homozygous for the allele associated with lower plasma IL-6 levels required higher doses of opioids. To our knowledge this is the first study to provide empirical evidence of the important role of IL-6 −174G/C
in analgesic response in cancer patients.
induces analgesic effects in animal models of inflammation (26
). Preclinical data first provided insight on the possible role of IL-6
in differences in opioid analgesia requirement. Bianchi et al. showed that IL-6
knockout mice had a reduced analgesic response to restraint stress. They also showed that the development of tolerance to the analgesic effect of morphine was more rapid in IL-6
–deficient mice and was accompanied by a reduction in the number of opioid receptors in the midbrain (19
). Glial activation in response to chronic opioid use has also been suggested to lead to the production of cytokines contributing to the apparent loss of opioid analgesia effectiveness upon repeated opioid administration (tolerance) and leading to the development of opioid dependence (27
). Spinal administration of IL-6 to rats with nerve injury has also been shown to result in antinociceptive effects, suggesting its potential as a modulator of pain (28
). Clinical studies also show that patients with pain have elevated IL-6 levels (29
We also observed a significant association with polymorphisms in TNF-308G/A
and pain severity. The −308 polymorphism is a G → A substitution and reportedly affects gene expression, the rare A allele resulting in higher TNF
has been suggested to be critical for the development of inflammatory pain behavior in animal models. Blocking TNF signaling inhibits the development of mechanical allodynia and inflammatory pain. The novel therapeutic potential of TNF inhibitors has also been suggested for conditions such as brain cancer, epilepsy, and chronic pain (31
). Anti-TNF therapy has also been shown to be profoundly analgesic, with an efficacy similar to that of cyclo-oxygenase-2 inhibition and reduced astrocyte activity in collagen-induced arthritis (34
In the larger cohort whence this sample was drawn, we found that IL-8 −251T/A
was significantly associated with pain severity at presentation, before receiving any cancer therapy (7
). Although we also noted a trend for higher MEDD by polymorphisms in IL-8 −251T/A
in this follow-up study, we found that polymorphisms in TNF-α-308G/A
and IL-6 −174G/C
were the significant correlates of pain during treatment and analgesic response, respectively. These findings potentially suggest the role of different pathways in the biology of pain and therefore have important implications in the clinical epidemiology of pain and its treatment. Alternatively, these findings may be viewed as arising from differences in methodology, e.g., the present analysis focuses on a subsample of the patients under chronic opioid therapy, who have had large doses of opioids, or the small sample (thus low power) may account for not detecting associations found in the first study. Nevertheless, taken together, these two studies suggest the importance of cytokines in the biology of pain and warrants further studies.
We also observed sex differences in the association between genotype groups and pain as well as for morphine dose. Specifically, we observed statistically significant differences in pain severity by TNF genotypes for men and by IL-6
genotypes for women and also observed that men with IL-6 −174CC
genotypes needed the highest morphine dose. However, these differences did not persist in the multivariable analyses. Studies have shown sex differences in pain and analgesic responses (20
). For example, there are sex differences in μ and κ opioid receptors with greater μ opioid responses in men and greater κ opioid responses in females (23
). Examination of sex differences in cytokine polymorphisms and their relations to pain and analgesic responses should be further explored for the development of individualization of pain treatment.
It is important to note that we found that many of our patients who presented with severe pain at initial consultation still reported severe pain at follow-up (from 41% to 21%) despite opioid therapy. Given that opioids have debilitating side effects, finding potential genetic markers of opioid response would help in preventing unnecessary suffering in opioid-resistant patients.
Previous studies have also shown that psychological distress, presence of neuropathic pain, delirium, and addictive behaviors are markers of poor prognosis for pain control. In our sample, we found that the presence of addictive behavior, defined by CAGE positivity, was associated with the need for greater opioid dosages. However, this association did not persist in the multivariable analyses.
Our study has potential limitations. Variants in other cytokine genes that have been shown to modulate pain in other disease conditions (for example, IL-1
and back pain; ref.35
) were not assessed in this study. Further, because IL-6
has both proinflammatory and anti-inflammatory effects, further elucidation of the mechanism by which it affects pain and analgesia is needed. It should also be noted that pain and inflammatory response is a complex process and numerous genes are likely involved. In the most likely clinical application, a combination of multiple polymorphisms would be more likely to be useful as predictors of pain and response to analgesia.
Among the strengths of our study is the assessment of several factors shown to be important in guiding pain treatment. Specifically, we evaluated stage of disease, sex, age, and comorbid conditions. In addition, the population we studied was a group of advanced-stage lung cancer patients referred to a Supportive Care program who all underwent structured symptom assessment and medication review. Although we have a small sample, subjects were not selected based on clinical pain criteria, thus reducing the possibility of selection bias. We could also assert that our study population (e.g., more male patients, the mean age of 60 years, and more advanced cancer patients) is similar to the general lung cancer population as reported in other studies (36
In conclusion, pain is a complex trait, with several pathways as potential candidates for studying genetic influences. For example, drug metabolizing enzymes, drug transporters, and opioid receptors (37
) or cyclo-oxygenases, or pathways involved in the perception and processing of nociceptive information (38
), the modulation of the pharmacokinetics or pharmacodynamic effects of analgesics have been explained by genetic factors. We hopefully contributed to this understanding by showing in a preliminary analyses the potential influence of cytokine genes on pain and response to analgesia in lung cancer patients receiving pain treatment and control from Supportive Care specialists. Our findings need to be validated in large prospectively accrued populations and incorporating additional genetic markers in the cytokine pathway.