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Understanding the Underlying Mechanisms of Pain in Patients With Cancer

A Conversation With Tony L. Yaksh, PhD


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Pain is among the most difficult medical issues for oncologists to confront, said Tony L. Yaksh, PhD, Professor of Anesthesiology and Pharmacology at the University of California, San Diego, during his keynote address at the 2019 Supportive Care in Oncology Symposium. Failure to adequately manage the intense pain from cancer and its treatment, according to Dr. Yaksh, can have serious psychosocial ramifications for patients, including diminution of quality of life, depression, and anxiety, as well as myriad physical consequences, such as hypertension, myocardial ischemia, suppression of gastrointestinal motility, and reduction in physical activity leading to joint and muscle deterioration.

Tony L. Yaksh, PhD

Tony L. Yaksh, PhD

Cancer-related pain is so ubiquitous; between 20% and 50% of patients with early-stage cancer will experience pain,1 and up to 90% of patients with advanced-stage cancer will develop severe pain.2 In addition, as many as half of cancer survivors will continue to experience pain and functional limitations long after their treatment has ended.3 Pain is also among the most-feared aspects of a cancer diagnosis.4

Although cancer-related pain is a complex biologic phenomenon that is not completely understood, new perspectives on the biology of pain caused by malignant tumors invading the body are emerging. It is now believed that cancer-related pain is a result of processes that involve cross-talk between neoplastic cells and a patient’s immune and peripheral and central nervous systems, and it is increasingly seen as different from other pain states.

“NSAIDs have little or no effect on pain events that are secondary to nerve injury, and opiates are less efficacious against a neuropathic condition.”
— Tony L. Yaksh, PhD

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In a wide-ranging interview with The ASCO Post, Dr. Yaksh discussed the origins of pain; effective therapies, including mindfulness approaches, to manage the condition; and advances in the development of more effective spinally delivered medications.

Causes of Cancer-Related Pain

How does cancer-related pain differ from pain caused by other diseases or injuries?

The problem with pain in cancer is undeniably complicated.2-6 To start, we often think that pain has three mechanistic phenotypes: acute, for example, when you burn your hand on a hot coffee cup, which acutely activates pain fibers; events secondary to tissue injury and inflammation, leading to ongoing pain and the development of facilitated pain states (hyperalgesia); and those states generated by injury to the nerve (neuropathic).

Each one of these states reflects upon different aspects of the mechanisms through which pain is encoded and transmitted within the spinal cord and brain. Now, think of the complexity of the impact of a tumor on the tissue. There is the effect of the tumor itself (its space-occupying, mass-distorting tissue and compressing nerves); products released by the tumor, which can activate pain fibers; and then the consequence of the immune response to the tumor, which may lead to antibodies that directly affect nerves. Thus, patients with cancer face the results of enabling virtually every component of the systems that lead to a pain message. In addition, there is the pain input arising from treatment interventions such as surgery, radiation, and chemotherapy, which are necessary for managing the cancer, but can also generate significant problems and contribute in their way to the pain state of patients with cancer.

Furthermore, cancer is not a single entity and may arise from the effect upon more than one system, including visceral pain from cancers of the pancreas, liver, colon, and prostate; bone pain from osteosarcoma; and central nervous system tumors that compress the spinal cord or the brain.

GUEST EDITOR

Addressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD, FASCO. Dr. Von Roenn is ASCO’s Vice President of Education, Science, and Professional Development.

Jamie H. Von Roenn, MD, FASCO

Jamie H. Von Roenn, MD, FASCO

Finally, an important advance in our understanding of pain is that the spinal input to the brain does not travel just to brain areas that reflect our sense of where and how intense the pain is, but to forebrain areas that integrate somatic input with the richness of learned associations. These forebrain areas are part of the older limbic forebrain and mediate processes underlying affect and emotion.

Thus, the brain has specific areas where the sensory-discriminative component of sensation is mediated, and there are areas that mediate the orthogonal component of affect and motivation. Here, the patient suffering from a life-threatening disorder brings the spinal pain input to those areas of the brain that remind us of our worries and concerns, for example, “Who will pay the mortgage and take care of the children?” and mortality. Such processes lead to pain states that are more than just the results of the sensory message. Thus, it is not surprising for patients with cancer to have one of the most complex pain states imaginable.

The pain states that arise from the disease can be variable depending on the type of cancer. The actual pain condition may likely change over time. Patients may go from a mild pain state during the early stages of cancer to increased pain as the cancer progresses. For example, in osteosarcoma, the cancer can progress to the point that the patient develops decalcification and destabilization of bone, which produce structural pressures on the innervation of bone. We think of bone as being a big piece of calcium, but it is an incredibly innervated organ.

In the case of bone cancer, the tumor cells growing in the marrow are secreting powerful materials in their ability to activate those sensory fibers going into the bone. So, you have a situation in which the pain state worsens with time, partly because the tumor is not only activating the sensory axons that are going into the bone, but destabilizing bone as well, with decalcification generated by the tumor microenvironment.

Choosing Effective Pain Medications

What are the most effective treatment strategies to alleviate pain for these different mechanisms?

Pain caused by acute inflammation may respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Bone cancer is surprisingly responsive to NSAIDs, at least in the early phase of the disease, because inflammation plays such a big role in that type of cancer. However, NSAIDs have little or no effect on pain events that are secondary to nerve injury, and opiates are less efficacious against a neuropathic condition. So, it is not surprising for a patient with a painful cancer to be prescribed three or four pain medications, including an NSAID, gabapentin for nerve pain, and opiates. All of them have different pharmacology and attack the pain processing through different mechanisms.

As for opiates, there is no doubt that opioids have been overprescribed, causing an addiction crisis in this country, but the whole reason opiates became so widely used in the medical community was because of the incredible efficacy of morphine in managing late-state cancer. This experience taught providers that if morphine is good for severe cancer pain, maybe it is good for nonmalignant pain, and we did not put the brakes on soon enough to stop the abuse of this medication. Just because a patient has a twisted ankle does not mean he should be given an opiate to relieve that pain.

The irony is that the benefit of opiates to patients with cancer cannot be overestimated. I am not a clinician, so I would be the last person to offer prescribing advice to oncologists regarding the use of opiates in cancer-related pain, but the notion that opiates are always unwise is overstated. There are many problems with opiates, including tolerance and side effects, but many patients with cancer benefit from them.

Practicing Mindful Meditation to Relieve Pain

In your presentation at the 2019 Supportive Care in Oncology Symposium, you talked about the beneficial role of mindful meditation and hypnosis to reduce the intensity of pain. How can these practices alleviate cancer-related pain?

There is growing evidence that how people look at life may be strongly impacted by their thought processes. I am no expert in the efficacy of mindfulness practices, but there is no doubt that meditation can help address many issues. Pain, generically, whether from cancer or another illness, has, as I mentioned previously, two broad components: sensory-discriminative (where does it hurt?) and affective-motivational (how bad is the threat?).

“Researchers like me who study pain have an incredible respect for oncologists who manage these chronic conditions.”
— Tony L. Yaksh, PhD

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Mindfulness approaches, such as meditation and hypnosis, can assist patients, at least in part, to cognitively “reconstruct” their perception of pain. It has been demonstrated that mindfulness practices have reduced limbic forebrain activation, increased tolerability to the stimulus environment, and reduced pain intensity. Study findings using magnetic resonance imaging to compare brain-behavior response to mindfulness-based stress reduction training demonstrate there is a reduction in response to pain intensity and covariance with reduced unpleasantness in the prefrontal cortex. These findings suggest mindfulness training may modulate the brain network dynamics underlying the experience of pain.7

Advancing Palliative Pain Management

What is the future direction of palliative pain management in oncology care?

There are enormous benefits to palliative pain management, including the use of opiates, which carry a lower risk of misuse by patients with cancer than by the general population. We and others are also developing interventions to deal with disrupting pain signals in the spinal cord, for example, injecting adenoviruses, toxins, and oligonucleotides to knock down systems associated with the process of pain.

There is no doubt we are clearly on the right track when it comes to altering the message coming from the spinal cord regarding pain to the brain. Then there is the great unknown of selectively altering higher-order function, perhaps with the hope of managing distress evoked by a noxious stimulus condition, such as cancer, without altering other aspects of emotionality.

These directions of study are important, and I think the promise is there to find effective solutions to assist physicians in their efforts in managing cancer-related pain.

Closing Thoughts

Researchers like me who study pain have an incredible respect for oncologists who manage these chronic conditions. They face the enormous challenge of helping patients improve their quality of life by controlling patients’ pain state, recognizing that patients are dealing not only with the physical aspect of their cancer, but with the emotional recognition of their own mortality as well.

In the end, the work we are doing in pain management research is to find a superior way to help clinicians deal with the problems their patients face. We take our cues from the clinicians trying to manage the care of these patients. 

DISCLOSURE: Dr. Yaksh reported no conflicts of interest.

REFERENCES

1. Fischer DJ, Villines D, Kim YO, et al: Anxiety, depression, and pain: Differences by primary cancer. Support Care Cancer 18:801-810, 2010.

2. Falk S, Dickenson AH: Pain and nociception: Mechanisms of cancer-induced bone pain. J Clin Oncol 32:1647-1654, 2014.

3. Harrington CB, Hansen JA, Moskowitz M, et al: It’s not over when it’s over: Long-term symptoms in cancer survivors—A systematic review. Int J Psychiatry Med 40:163-181, 2010.

4. Lemay K, Wilson KG, Buenger U, et al: Fear of pain in patients with advanced cancer or in patients with chronic noncancer pain. Clin J Pain 27:116-124, 2011.

5. Knezevic NN, Yekkirala A, Yaksh TL: Basic/translational development of forthcoming opioid—and nonopioid—targeted pain therapeutics. Anesth Analg 125:1714-1732, 2017.

6. Mantyh PW: Bone cancer pain: From mechanism to therapy. Curr Opin Support Palliat Care 8:83-90, 2014.

7. Zeidan, F, Baumgartner JN, Coghill RC: The neural mechanisms of mindfulness-based pain relief: A functional magnetic resonance imaging-based review and primer. Pain Rep 4:e759, 2019.


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