Imagine living every day with pain so intense that even the simplest activities become torture. For up to 90% of all cancer patients in advanced stages of the disease, this is a sad reality 1 . In Germany, an estimated half a million people are affected by tumor pain, which in 20-40% of patients is even among the first warning signs of the disease 1 .
But what causes this agonizing pain, and how can modern medicine provide relief? The answer lies in a fascinating interplay of molecular biology, pain research, and palliative care, which together have found ways to alleviate suffering. Particularly groundbreaking are recent findings showing that tumors can actively send pain signals - a discovery that promises completely new therapeutic approaches.
Scientists are investigating how tumors actively modify the nervous system to create pain signals, going beyond simple mechanical pressure.
Modern palliative care combines pharmacological interventions with psychosocial support for comprehensive pain management.
Cancer causes pain through various mechanisms. Most common is tumor-related pain, where the growing tumor irritates surrounding tissue or presses on nerves 4 . Physicians distinguish between nociceptive pain (caused by tissue irritation) and neuropathic pain (caused by nerve damage) 4 . Particularly severe pain occurs when metastases settle in the bones, as is often the case with prostate, breast, lung and colon cancer 4 .
Caused by activation of pain receptors due to tissue damage, inflammation, or pressure from tumor growth.
Caused by damage to or dysfunction of the nervous system itself.
But cancer doesn't just hurt because it takes up space. Modern research shows that tumors actively send messenger substances that sensitize our nervous pain system 2 . These messenger substances make nerve cells hypersensitive - they then react to harmless stimuli with strong pain signals. This vicious cycle explains why some patients suffer agony even with light pressure or even without any recognizable trigger.
In palliative medicine, the concept of "Total Pain" has been established, describing the multidimensional nature of suffering at the end of life 5 . It includes:
The purely sensory perception of pain
Anxiety, depression, despair
Isolation, relationship problems, financial worries
Questions of meaning, life crises, religious needs
This holistic understanding explains why successful pain therapy today never only involves the administration of medication but always has the treatment of all dimensions of suffering in mind.
A milestone in the research of tumor pain was achieved by scientists at Heidelberg University Hospital and the German Cancer Research Center around Professor Dr. Rohini Kuner and Professor Dr. Hellmut Augustin 2 . The researchers investigated why certain tumors - especially pancreatic cancer and bone metastases - are particularly painful, while others, such as some forms of breast cancer, cause hardly any discomfort.
Their attention focused on a receptor protein called VEGFR1, which occurs on the surface of nerve cells. Receptors are like specialized antennas that capture certain signal molecules and trigger a reaction in the cell. VEGFR1 reacts to growth factors (VEGF) that the tumor releases to ensure its blood supply.
The Heidelberg researchers proceeded in a series of precise experiments:
They examined the pain behavior of mice with tumors
They specifically blocked either VEGFR1 or the related VEGFR2 only in nerve cells
They tested pain sensitivity through touch stimuli
They analyzed tumor tissue from pancreatic cancer patients with different pain levels
The results were astonishing: Without a functional VEGFR1 receptor, hardly any pain sensitization occurred, while switching off VEGFR2 had no effect 2 . Even more significant was the analysis of human tumor tissue: The stronger the tumor pain of the patients, the more VEGFR1 was found on their nerve endings 2 .
| Pain Group | VEGFR1 Amount on Nerve Cells | Pain Sensitivity |
|---|---|---|
| Low Pain | Low | Normal |
| Medium Pain | Medium | Increased |
| High Pain | High | Strongly Increased |
Table 1: Pain intensity depending on VEGFR1 amount in pancreatic cancer patients
The identified mechanism can be summarized as follows:
Tumor releases VEGF growth factors
VEGF binds to VEGFR1 on nerve cells
Receptor activation triggers signaling
Nerve cells become hypersensitive
Pain signals without recognizable trigger
| Receptor | Function in Nerve Cells | Pain Relevance | Effect on Blood Vessels |
|---|---|---|---|
| VEGFR1 | Pain sensitization | High | No known direct effect |
| VEGFR2 | Unknown | Low | Crucial for angiogenesis |
Table 2: Comparison of VEGF receptors and their function in nerve cells
The research of tumor pain requires a diverse arsenal of methods and reagents. The following table summarizes the most important tools used in experiments like the VEGFR1 study:
| Reagent/Method | Function | Application in Experiment |
|---|---|---|
| Animal Models (Mice) | Recreating human tumor diseases | Examination of pain behavior and molecular mechanisms |
| Cell Lines (Leukemia, glioma cells) | In-vitro studies of tumor cells | Analysis of cellular signaling pathways |
| Receptor Blockers (VEGFR1 inhibitors) | Targeted inactivation of specific receptors | Functional analysis of individual receptors |
| Immunohistochemistry | Visualization of proteins in tissue samples | Quantification of VEGFR1 in human tumors |
| Pain Assessment Tools (NRS scale) | Standardized pain measurement | Classification of patient pain |
| Genetic Modification | Targeted alteration of genes | Production of receptor-deficient models |
Table 3: Research reagents and their application in tumor pain research
In clinical practice, the WHO step scheme has proven extremely effective. It provides for a gradual use of painkillers, starting with non-opioids such as metamizole or ibuprofen and, if necessary, gradually progressing to strong opioids 4 . Crucial is the regular intake "by the clock", not only when pain reappears 4 .
NSAIDs, Paracetamol, Metamizole
For mild to moderate pain
Tramadol, Tilidine, Codeine
For moderate to severe pain
Morphine, Oxycodone, Fentanyl
For severe to very severe pain
Adjuvant medications can be added at any step to address specific pain types or side effects. These include antidepressants, anticonvulsants, corticosteroids, and bisphosphonates.
Opioids are among the most effective painkillers but are surrounded by misunderstandings. In contrast to over-the-counter painkillers, opioids are not organ-damaging with long-term use 4 . However, they have other side effects such as nausea (usually only at the beginning) and constipation (often permanent), which can however be treated well with medication 4 .
The fear of addiction is largely unfounded when used correctly in the context of pain therapy 4 . As one expert emphasizes: "Good pain therapy promotes quality of life and thus supports cancer therapy" 4 .
In media reports, methadone has been repeatedly touted as a miracle cure against cancer. The German Pain Society, however, makes it clear: A prognosis improvement through methadone is not scientifically proven . Although experiments in cell cultures and in mice show tumor-inhibiting effects, these have so far not been transferable to the treatment of patients .
Methadone has its fixed place in pain therapy, but not as an oncological therapeutic. An uncritical use outside approved indications is to be rejected due to the considerable risks (respiratory depression, QT prolongation, accumulation risk) .
"A good pain therapy promotes quality of life and thus supports cancer therapy."
The research on tumor pain is developing rapidly. Particularly promising are investigations into genetic variability as a predictor for the effectiveness of opioids 1 . Could a genetic test in the future reveal which painkiller works best for which patient?
Research focuses on genetic markers that predict individual responses to pain medications, allowing for tailored therapy.
Pharmacogenomics Biomarkers Genetic TestingStudies explore how tumors interact with the nervous system at molecular levels to develop targeted interventions.
Signal Pathways Receptor Targets NeuromodulationAlso the neurobiology of tumor pain is intensively researched 1 . The discovery of the VEGFR1 mechanism is only a first step. Scientists are already working on substances that specifically block this receptor and thus could interrupt the pain-sensitizing effect of the tumors - without damaging the blood vessels, as is the case with general VEGF blockers 2 .
Drugs that specifically block pain-sensitizing receptors like VEGFR1 without affecting angiogenesis.
Spinal cord stimulation and other neuromodulatory techniques to interrupt pain signals.
Advanced formulations for better drug targeting and reduced side effects.
The research and treatment of tumor pain has achieved remarkable progress in recent years. From understanding molecular mechanisms to developing holistic therapy concepts, science is improving the quality of life of hundreds of thousands of patients. The greatest strength of modern palliative medicine lies in its integrative approach: It combines pharmacological top research with psychosocial care and treats the person in their entirety - not just their illness.
Even if many questions are still open, one thing is certain: The scientific engagement with tumor pain has developed from a marginal topic to an innovative research field that is increasingly experiencing destigmatization and whose insights enable millions of patients worldwide a dignified life despite cancer diagnosis.