Cancer Pain

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Introduction

The incidence of cancer worldwide is 18 million cases per year. 55% of the patients undergoing treatment for cancer experience pain. Despite the improvement in early detection and treatment of cancer, progress related to Cancer Pain management is mostly inadequate. Cancer Pain is still a major concern and affects the quality of life. A barrier to efficient cancer pain management still exists. Lack of knowledge regarding cancer pain assessment and its management is pervasive among practitioners. Cancer patients' pain may be caused by direct tumor involvement, diagnostic or therapeutic procedures, side effects, or toxicities of cancer treatment.

Types of Cancer Pain

Neuropathic pain 

It is caused by pressure or trauma to the somatosensory system. It may lead to loss of function and increased pain sensitivity and spontaneous pain. It is common in cancer and is usually chronic, either persisting continuously or characterized by recurrent painful episodes. Research suggests a higher prevalence of 40%.

Damage by primary tumor or metastases

It may result from direct infiltration by the primary tumour or metastases into the peripheral or central nervous system components. For example, invasion of the brachial plexus by thoracic tumors or invasion of the lumbosacral plexus by abdominal or pelvic tumors affecting the peripheral nervous system. Or spinal cord compression resulting from vertebral collapse due to bony metastatic disease involving the central nervous system.

Treatment-related damage

Cancer therapy-induced neuropathic pain can result from side effects or complications from cancer treatments: surgery (direct trauma to the peripheral nerves), radiotherapy, and chemotherapy.

Surgery:

Interventions commonly associated with post-traumatic neuropathic pain syndromes include mastectomy and thoracotomy.

Radiation-induced neuropathy:

It can cause chronic painful radiation-induced neuropathy. Delayed local damage to the nervous system due to radiotherapy is common, sometimes manifesting months or even years following treatment. It is often progressive and irreversible, resulting from nerve compression from radiation-induced fibrosis or direct nerve and blood vessel injury from microvascular changes.

Chemotherapy-induced peripheral neuropathy (CIPN):

A common, painful, dose-dependent, and dose-limiting side effect of chemotherapy. CIPN is caused due to direct neurotoxic effects of chemotherapy on dorsal root ganglion neurons or their axons, causing pain in a stocking-and-glove distribution, sensory loss, and sensory ataxia. The pain is often described as pricking or burning, or an “electric sensation”. Autonomic, motor, and occasionally cranial nerve involvement can less commonly occur. Typically, symptoms appear in the first two months of treatment and worsen as treatment progresses and then stabilise soon after stopping treatment. However, symptoms can persist long after treatment. Common neurotoxic chemotherapeutic medications include the taxanes (paclitaxel and docetaxel), platinum-based drugs (cisplatin and oxaplatin), vinca alkaloids (vincristine), thalidomide, and proteasome inhibitors (bortezomib).

Bone pain

80% of bone cancer metastases results from cancer of the breast, lungs, and prostate. The relative incidence of bone metastases is 65–75% in breast cancer, 65–75% in prostate cancer, 60% in thyroid cancer, 40% in bladder cancer, 20–25% in renal cell carcinoma, and 14–45% in melanoma. 65% of all bone metastases originate from breast cancer (in women) and prostate cancer (in men). The remaining 35% of metastasis arise from cancer of the kidneys, thyroid, and lungs.

Patients initially encounter intermittent dull aches, but the pain becomes constant and more severe as the disease progresses. Its intensity cannot be determined by the tumor type, the tumor size, the number of metastases, or bone involvement  Pain is seen near the area of metastatic bone lesions. The pain aggravates with movement, often increasing at night. It can be accompanied by fever.

Oro-facial pain

Orofacial pain (OFP) may be caused by direct cancer involvement of anatomical structures, the side-effects of cancer treatment or patient comorbidities. OFP is reported by approximately half of HNC patients before oncology therapy, 81% during treatment, 70% at the end of treatment, and 36% six months after treatment.

Causes of OFP

• Oral mucositis and stomatitis are common acute adverse effects of combined chemotherapy and radiotherapy (CRT). Incidence of severe mucositis ranges between 60% and 90%, and it significantly increases pain during anti-cancer treatment.
• Temporomandibular disorders (TMD) frequently affect HNC patients. Trismus is a TMD resulting from the impairment of the masticatory muscles, a late complication of head and neck radiotherapy.
• Burning mouth syndrome (BMS) and painful post-traumatic Trigeminal neuropathy, chronic neuropathic conditions characterized by unilateral or bilateral facial or burning oral pain of the tongue and other parts of the oral mucosa, may result due to nerve damage induced by CRT.

Phantom Pain

The phantom phenomenon consists of three distinct elements:

1. Phantom limb pain (PLP): Painful sensations referring to the amputated limb.
2. Phantom limb sensation (PLS): Sensations other than pain that are being referred to the amputated limb.
3. Stump pain (SP): Pain localized to the amputated stump.

Research suggests that phantom limb pain following cancer-related amputation in children and young adults is common but short-lived in most patients.

Pain Mechanisms in Cancer Pain

Central sensitization

A "spontaneous or ongoing” pain indicates central pain mechanisms. There is increased sensitivity of higher-order neurons of the central nervous system, which causes pain in the absence of a peripheral nociceptive stimulus.

Peripheral sensitization/peripheral neuropathic mechanism

Pain is caused by a primary lesion or dysfunction in the peripheral nervous system (PNS). Caner-related: Brachial plexus neuropathies, chemotherapy-induced neuropathy, cranial neuropathies, post-radiation plexopathies, and surgical neuropathies.

Sympathetic pain

Cancer pain is associated with over- or under-activation of the sympathetic nervous system. Sympathetic dependent pain (SDP) or sympathetic maintained pain (SMP) is characterised by cutaneous dysesthesia accompanied by sympathetic overactivity.

• "Burning” and “throbbing” sensations are present with allodynia (pain caused by a non-noxious stimulus and often tested by light touch), hyperpathia (delayed pain response to touch stimulus) and hypoalgesia to pinprick testing in the painful area.
• Signs of excessive sweating and vasoconstriction (pale, cold, white extremities) show sympathetic overactivity; often observed in lower limbs, chest, head and neck, and rarely in upper extremities.

Nociceptive mechanisms

Nociceptive pain in cancer patients could be due to disuse, deconditioning and abnormal movements or postures adopted by a cancer patient.

Cognitive-affective mechanisms

Patients with cancer pain showed higher levels of anxiety and depression. Cognitive-affective dysfunction in cancer pain could be because of cancer or treatment associated with the disease like narcotics and opioids prescribed.

Assessment

The National Comprehensive Cancer Network (NCCN) has created guidelines on assessing and managing cancer-related pain in the adult oncologic population. A comprehensive pain assessment includes evaluation of the pain intensity, the etiology, and pathophysiology of pain, and identifying what the patient identifies as a goal pain score or functional outcome.

The clinicians should take a proper pain history. He/she should ask the patient regarding the patterns of pain score (high/low/average) and the effect of analgesic on the pain over time rather than only focusing on the pain present at the time of the evaluation.

The intensity of pain can be measured by:

• A cognitively intact patient may be able to rate pain on the Numerical Rating Scale of 0 (no pain) to 10 (worst pain imaginable). Alternatively, some patients may use a categorical scale or visual analog scale (no pain, mild pain, moderate pain, or severe pain).
• Patients with diminished cognition may not provide a verbal pain history but can provide information that can guide the treatment plan. Clinicians should look for nonverbal signs of discomfort (like agitation, irritability, restlessness, grimacing, or confusion). Patients who are verbal but have impaired memory may not provide a reliable pain history for how they felt in the past, so providers need to focus on the level of pain reported during the meeting. Patients with severe cognitive impairment may not show characteristic behavioral responses to pain. In these cases, clinicians should use their judgment to consider whether a cognitively intact patient with similar disease burden would be expected to report pain and if so the clinician should initiate a symptom treatment plan and monitor for the response. Clinicians should not assume the absence of pain simply because the patient is unable to provide a classic verbal pain history.

Pain Management

Pharmacological treatment

After a comprehensive pain assessment is completed, a multimodal management plan can be implemented. Setting the appropriate expectation for patient is the primary step in pain management as the cause of pain would influence the outcomes and treatment adherence. For example, in case of pain emanating from local tumour or fracture, improvement is seen as the disease is treated, whereas in chronic neuropathy the course takes a longer time.

World Health Organization (WHO) Analgesic Ladder.

The WHO ladder consists of a stepwise approach to guide clinicians through a systemic approach to pain management. The choice of analgesic is determined by the severity of pain.

• Step 1: consists of using over-the-counter analgesics to manage pain (e.g. acetaminophen, NSAIDs)
• Step 2: escalates to using medications traditionally considered “weak” opioids (e.g. codeine)
• Step 3: recommends the use of stronger opioids
• Step 4: consists of the use of interventions for non-pharmacologic management options for pain

While the WHO Analgesic Ladder is effective in treating cancer pain in a majority of patients, a current debate about whether these guidelines remain the optimal way of treating pain in all patients exists. Newer research suggests that patients with moderate pain secondary to cancer are more likely to respond to low-dose morphine than they are to codeine, questioning the need to try “weak” Step 2 opioids prior to initiating morphine for control of moderate pain especially considering there were no differences in adverse effects between the two groups.

NON-OPIOID treatment:

Acetaminophen

Acetaminophen is the first-line treatment in patients with mild cancer pain who may not require an opioid or may be hesitant to use an opioid. If adequate analgesia is not achieved with acetaminophen alone clinicians should consider switching to opioids for pain management. Besides, the use of acetaminophen in cancer patients is limited by hepatotoxicity, especially in patients with liver disease. Also, there is a need for close monitoring for fevers in patients with neutropenia.

NSAIDs

Safety considerations exist when using NSAIDs: bleeding, pre-existing renal impairment, risk of precipitating renal impairment in patients with multiple myeloma, increased risk of hypertension. There are mixed views on the benefits of using NSAID with opioids; some studies showing a benefit to the combination while other studies showing minimal to no difference when comparing the use of an NSAID plus opioid to either class of drug being used alone.

Adjuvants medications

• Antidepressants: Pathophysiology of neuropathy is complex and affecting receptors for norepinephrine, serotonin, opioids, and N-Methyl-D-aspartic acid (NMDA), so some antidepressants with activity at these receptors can be effective in treating neuropathic pain. For e.g. tricyclic antidepressants (TCAs), duloxetine.
• Anticonvulsants: like Gabapentin and Pregabalin are effective in managing neuropathic cancer pain.

Interventions

Interventions are helpful when patients have inadequate pain control with systemic analgesics, intolerable side effects, or if additional barriers towards opioids prevent adequate usage.

• Epidural/Intrathecal Analgesics: Medicines that cannot be given orally can be administered through this intervention. Also, different classes of drugs can be given simultaneously. Contraindications to spinal procedures in patients with risk of bleeding, infection, or local tumor burden.
• Nerve blocks: Recent evidence shows that interventions may be more effective when considered earlier in the disease course

Integrative therapies

• Acupuncture: Studies suggest acupuncture has a role in the management of cancer pain, and guidelines exist to treat cancer pain with acupuncture. Since the results obtained with acupuncture therapy are mixed with some studies showing a decrease in pain while others suggesting no significant difference between acupuncture and conventional treatment, clinicians should discuss potential risks and benefits with each patient on an individualised basis.
• Mindfulness: is an important tool for patients’ pain management with mindfulness meditation influencing pain attenuation.

Cannabis or Medical Marijuana

Cannabinoids are efficient in cancer pain, which is not entirely relieved by opioid therapy, but more research is needed to support a more definite conclusion. Cannabinoids are safe in low and medium doses.

Opioids

As per the WHO analgesic ladder, Step 2 or 3 opioids can be started when analgesia is not achieved by over-the-counter analgesics (i.e., morphine, hydromorphone, or oxycodone).

Side-effects: Mild nausea, constipation, sedation, agitation or delirium. 

Chronic Opioid use

In Chronic opioid therapy (COT), treatment duration exceeds three months, then there is an increased risk of endocrinopathies, depression, sleep-disordered breathing, impaired wound healing, substance use disorders, and cognitive impairment with chronic opioid therapy. It is often a challenging task to strike a proper balance between analgesia and minimizing the risks associated with COT. Early implementation of psychological interventions, consideration of interventional and neuromodulatory therapies, close monitoring with frequent follow-up visits, the use of naloxone for high-risk patients, and tapering of the opioid therapy are common strategies used in treatment.

Role of neuro-modulation in pain relief

Neuro-modulation is an electrical or chemical alteration of signal transmission within the nervous system by using implanted devices or—increasingly—non-invasive techniques, which results in a modulation of pain signals leading to analgesia. It comprises various therapies that range from the more widely used such as spinal cord stimulation (SCS), neuraxial drug delivery systems, and peripheral nerve stimulation (PNS) to new and less examined treatment modalities, including deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, or motor cortex stimulation.

Spinal cord stimulation

Use of high-frequency (10 kHz) stimulation that provides pain relief without the typical paresthesias experienced in the standard low-frequency SCS. Dorsal root ganglion (DRG) stimulation containing cell bodies of primary afferent nociceptive nerve fibers may benefits patients with neuropathic pain syndromes (for example, chronic postsurgical pain, which affects many patients with cancer),

Neuraxial drug delivery systems

The treatment involves the infusion of one or more drugs into the epidural or intrathecal (IT) space. Implantable intrathecal IT pump therapy is a viable, safe, and effective way of managing intractable CP. But higher cost and lack of familiarity with IT pump among oncologists make its utilization difficult.

Peripheral nerve stimulation PNS

PNS is an attractive modality for the treatment of neuropathic pain due to peripheral nerve injuries, nerve entrapments, or damage done to nerve plexuses. However, its application is quite limited.

Scrambler therapy

Scrambler therapy (ST) is a novel method and is used in the treatment of chronic pain, including CP. It was discovered by Italian biophysicist Giuseppe Marineo, who describes the pain system as an “information system” and believes that chronic pain can be controlled by modulating the afferent information aspects of pain.

Treatment involves stimulation of large and small fibers in peripheral nerves, the pathological information pain processes “are scrambled” and in effect, the brain is retrained not to perceive the treated area as painful. Many small studies have documented its effectiveness; however, large clinical trials are yet to be conducted. High treatment cost is a major drawback.

Transcranial magnetic stimulation

There is no evidence of the use of Transcranial magnetic stimulation in CP. This therapy can be an alternative treatment for CP as it is non-invasive and has good tolerability. A case study reports successful CP treatment in two patients in the palliative care setting.

Transcranial direct current stimulation

Transcranial direct current stimulation a very desirable complementary technique in the treatment of CP as it is non-invasive, easy to use, with excellent safety profile, and low cost. However, more studies defining the exact treatment protocols are needed for wider application in patients with CP.

Physiotherapy Management

Patient-centred therapy based on a mechanism-based approach is used in recent years. It includes identifying the dominant type of pain by differentiating between nociceptive, neuropathic, and central sensitization pain.

The therapeutic strategies used by physical therapists in palliative oncology are ambulation and musculoskeletal therapy, neurological therapy, respiratory therapy, electrophysical agents, mechanical therapy, decongestive physiotherapy, and education

Central sensitization mechanism-based physical therapy for cancer pain

Patient education

Treatment strategies should focus on attitudes, beliefs, and past experiences about pain. Knowledge about pain and cognitive strategies such as patient education has a positive impact on pain reduction.

Educational interventions (written and/or audiovisual learning materials) promote knowledge and attitudes toward cancer pain and analgesia, and perceived pain intensity among cancer patients. Pain educational programs are highly effective not only in reducing pain and associated pain behaviours, but also in reducing treatment-related barriers in cancer patients. One such method is the use of pain management diary.

Use of Pain Diaries: 

• Implementing pain diaries provide valuable insight into adherence to the analgesic regimen. Pain diary helps in documenting the frequency of medication use, time of day medications are taken, any side effects, concomitant symptoms, and the impact of pain on functional status.
• Pill counts are another informative tool if a patient’s cognitive status hinders their ability to provide a history.

Incorporating pain diaries and pill counts into routine clinical practice can reveal important information about patients and caregivers. Maintaining pain diaries improve patient empowerment and involvement in pain management while providing the clinician with insight into the triggers for opioid use (i.e., whether the opioid is being used for physical pain or emotional pain).

Pain-relieving modalities

TENS: It addresses the central component of cancer pain and is a very useful therapeutic adjunct in patients with central sensitization. Evidence for TENS in chronic pain such as phantom limb and stump pain, chronic pain conditions exists.

Nociceptive-mechanism-based physical therapy for cancer pain

Different modalities and conditioning exercises can be included to promote healing of injury and inflammation. Heat, cold, TENS, and interferential current; and conditioning exercises like stretching and flexibility exercises, massage, myofascial release, and joint mobilization are also very useful for relieving pain.

Massage therapy

According to various studies, Massage therapy is effective in relieving cancer pain. It helps in draining local tissue edema, improves local circulation, stimulates the free nerve endings. and induces local and general relaxation. Complete decongestive therapy (CDT) protocol involving manual lymphatic drainage, compression garments, skin-care, and range-of-motion exercises provided to 135 patients with lymphedema after breast cancer treatment reduced the volume of edema and pain significantly post-therapy.

Sensory re-education methods/Desensitization measures

neurodynamic testing 

Cold therapy

Cold therapy helps in reducing swelling and pain relief pain by decreasing the nerve conduction velocity and desensitization of free nerve endings of the skin. However, there is limited evidence of physical therapy management for sympathetic pain in cancer.

Laser therapy

Low-level laser therapy (LLLT) promotes pain relief and reduces OM incidence which is a common and severe acute side-effect of chemotherapy or radiotherapy in advanced head and neck cancer.

Exercises

Exercises improve quality of life, strength, and endurance and reduced depression, nausea, and pain. Studies in metastatic cancer patients suggest aerobic exercises and strength training have positive outcomes. Pilates exercises increased the range of motion of shoulder joint and reduced pain in women recovering from breast cancer treatments.

pilates

range of motion exercises

Graded activity

References

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