Cancer diagnosis and progression significantly reduces quality of life, emotionally, mentally and physically. Patients are often burdened by the severe side effects of toxic chemotherapy that impair patient quality of life (Wagland et al, 2016). Of the various symptoms related to cancer and its treatment, pain is one of the most underrated and undertreated (Torresan et al, 2015).
Effective management of pain in oncology enhances quality of life, improves adherence to treatment, and reduces the utilisation of healthcare facilities (Basch et al, 2016). There has been an improvement in the quality of pharmacological pain management, however, medication proportional to pain intensity is still not received by approximately one-third of patients (Greco et al, 2014).
The severity of pain varies with the stage of the disease and the type of cancer. Squamous cell carcinoma of the lung rarely presents with pain, whereas squamous cell carcinoma of the oral cavity almost always present with pain as the initial symptom (Schmidt et al, 2010). Despite years of research and technological advancement in understanding, detection and treatment, the progress related to cancer pain is slow and inadequate (Chwistek, 2017).
There is an immediate need for effective guidelines that include all viable treatment modalities and help clinicians in regulating the pain caused by cancer and its treatment. There is also a need to impart training to healthcare professionals, including nurses and paramedical staff, for executing better pain management tactics.
Pathophysiology
The two broad categories of pain are nociceptive and neuropathic. Results of laboratory tests, imaging studies, history, and physical findings play an important role in determining pain pathophysiology. The demonstrated pathophysiology of cancer pain helps in determining treatment for cancer pain management (Von Gunten, 2011).
Cancer pain may be caused either by the disease or treatment. The tumour can compress the nerve, bone or organ, causing moderate to severe pain. Various chemotherapeutic agents also cause sensory neuropathic pain. Of all the organ-specific cancer pain, the worst pain is seen in those who have bone cancer, due to cancer metastases (Garber, 2003). Because of the highly acidic environment generated by the osteoclast, ion channels are opened, leading to nerve firing, which ultimately results in pain signalling and sensation (Garber, 2003).
Cancer pain may be caused by the simultaneous action of inflammatory mediators and direct damage to sensory nerve fibres due to tumours, through compression or infiltration. Inflammatory mediators are generated by surrounding tissue damage and from the necrotic centre in large tumours (Falk et al, 2014).
Pain is generally related to the anatomical location of the tumour, its pathophysiology and the strategy adopted in the treatment of cancer. The cause of the pain may be neuropathic, visceral, somatic or composite (Thorp, 2019).
Neuropathic cancer pain is prevalent in as high as 40% of patients, and, apart from the direct invasion or nerve compression by the tumour, neuropathic cancer pain may also be caused due to various cancer treatments including radiotherapy, surgery and chemotherapy. There are various types of neuropathic cancer pain – knowing each type of pain improves diagnosis, treatment, and outcome (Yoon et al, 2018).
Prevalence
Despite increased attention, prevalence of pain in cancer patients has not significantly altered over the last decade, when compared to the previous four decades (Haumann et al, 2017).
A systematic literature review by Van den Beukenvan Everdingen and colleagues (2007) of a total of 52 articles showed that pain was prevalent in 64% of patients with metastatic or advanced-stage disease, 59% of patients suffer pain due to anticancer treatment, and pain was prevalent in 33% of patients after curative treatment. In the articles reviewed in the study, more than one-third of the patients graded their pain as moderate-to-severe. Another systematic literature review, published by Van den Beuken-ven Everdingen and colleagues 10 years later, indicates that little has changed in cancer pain prevalence, despite improvement in attention. A total of 112 articles, of which 78 studies have the primary aim to determine the prevalence of pain in cancer patients, were included in the study. The study shows a pain prevalence rate of 66.4% in advanced, metastatic or terminal disease and the prevalence rate during anti-cancer treatment was 55%. The pain prevalence rate after curative treatment was found to be 39.3%. Although the central nervous system may be affected by chemotherapeutic neurotoxicity, peripheral sensory neuropathy is the most common occurrence affecting 10–100% of patients, depending upon other underlying medical conditions, cumulative dosage and the type of chemotherapeutic agent (Park et al, 2013; Cata et al, 2006). Chronic severe pain in approximately 5–10% of cancer survivors significantly affects their functionality (Brown et al, 2014).
In a multicentre, cross-sectional study comprising 48 Italian hospitals, 1018 patients were analysed (Bandieri et al, 2010). It was shown that patients suffering from haematological malignancies have a high prevalence of pain. The analgesic therapy used for these patients was different from the therapy used in other malignancies at similar pain intensity. For instance, frequent use of non-opioids for haematological malignancies. In both solid and haematological tumours, fentanyl was the most frequent opioid used. The second most frequently used opioid was tramadol in haematological tumour patients and morphine in solid tumour patients (Bandieri et al, 2010).
In the European Pain in Cancer survey (Breivik et al, 2009), 5084 adult patients were contacted. 69% of the patients suffered from moderate-to-severe pain that affected their daily activities. There was a belief in 50% of patients that their quality of life was not considered a priority by their clinicians.
Treatment barriers
In the recent past, various novel analgesics have been developed. Several international medical associations such as the World Health Organization (WHO) and European Society of Medical Oncology have issued updated guidelines for effective and adequate cancer pain management. Despite these efforts, many patients with moderate-to-severe pain remain untreated. This is because the management of cancer pain is restricted by various barriers, including societal attitudes toward pain management, system and regulatory barriers, clinical barriers, patient barriers, and healthcare disparities (Scarborough et al, 2018).
From the evidence, it is apparent that lenient regulatory frameworks are not in place when it comes to prescribing opioids in the management of pain (Webster et al, 2015). Reasonable regulatory and moral guidelines should be designed to maintain transparency, while prescribing controlled substances. Keeping in view the risk of the opioid epidemic, which is felt across a person's lifespan and in every sociodemographic group, maintaining transparency is indeed required, but a more considered system should be in place so that those who need opioids are not deprived (Phillips et al, 2017).
The quality of pain assessment, prescription of opioids and physicians' knowledge of pain management guidelines is better in some Western countries. The healthcare system barriers are dominant in these countries, which have restrictive regulations in opioid prescriptions (Jacobsen et al, 2009).
These inadequacies are further noted in a study that explores barriers among nurses caring for oncology patients in Kenya (Onsongo, 2019). Almost 80% of patients with a malignant disease were found to experience untreated moderate-to-severe pain. The study specifically identified opioid-related fears, restrictive dispensing guidelines, absence of access to pain management guidelines and training as major barriers to effective pain management.
Pain management in oncology
Strategies used to manage pain due to malignant disease involves both medications and complementary techniques. Non-pharmacological therapies in cancer pain management include massage, yoga, meditation, and hypnotherapy (Singh et al, 2015). Relaxation techniques relieve pain through calming effects and break the pain-muscle-tension-anxiety cycle (Sloman, 1995). Other options for pain management include radiation therapy, interventions such as nerve blocks and intrathecal analgesics, and integrative therapies, such as mindfulness and acupuncture.
WHO (2013) has recommended a three-step ladder approach for effective management of cancer pain in adults. In step I, non-opioid analgesics are used, step II recommends the use of mild opioids such as codeine, and step III manages severe pain and recommends the use of potent opioids. Providing the right drug at the right dose at the right time manages pain in all cases. A drug should not be administered in response to a demand, instead they should be administered ‘by the clock’ at regular intervals (WHO, 2013).
In a study on 400 cancer patients aged above 18 years that were interviewed at the American University of Beirut Medical Centre surgical and medical oncology floors, outpatient clinics, and chemotherapy units, almost 46% of patients with cancer pain received inadequate treatment (Nadine et al, 2018). There is clearly still a lot to achieve in managing cancer-related pain.
Pharmacological interventions
The pharmacological interventions for cancer pain management can be customised, based on individual requirements.
Acetaminophen
Acetaminophen is generally not used alone for management of cancer pain, but in combination with various opioids (Nersesyan et al, 2007). However, a systematic literature review of the evidence of the benefit of paracetamol added to opioid therapy found it was ineffective in four out of five trials (Nabal et al, 2012). The hepatotoxicity profile of paracetamol also limits its use in the patients.
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the management of mild cancer pain, and are frequently used with opioids (McNicol, 2005). However, the ceiling effects of NSAIDs is a primary limitation, as the patient fails to achieve any relief as the dose is increased beyond a certain limit (Mercadante, 2001). Long-term use of NSAIDs requires the use of proton pump inhibitors for gastroprotection, thereby increasing the risk of kidney dysfunction and bone fractures (Strawson, 2018).
Because of the scarcity of robust data to indicate the efficacy of NSAIDs in treating cancer pain, the prescriber should plan the use of NSAIDs on a case-by-case basis.
Opioids
When paracetamol and NSAIDs have failed to provide adequate relief from cancer pain, opioid analgesics are added to the regimen, either according to step II or step III of the WHO pain management ladder.
Opioids are frequently used in the cancer pain setting because they have multiple routes of administration, and due to their safety, and efficacy in all types of pain, whether visceral, somatic or neuropathic (Portenoy et al, 2019). However, their use is also associated with drug abuse (National Institute of Drug Abuse, 2019). The lack of ceiling effects in opioids has contributed to the use of doses that are larger than normal in cancer patients (Vorobeychik, 2008).
When a patient is on strong opioid therapy, discontinuing paracetamol may not imply increased pain, rather the discontinuation of paracetamol indicates relief in pain, as there is a reduced tablet burden (Axelsson et al, 2008).
A study by Koizumi et al (2004) conducted on 22 Japanese patients with lung cancer, stomach cancer and oesophageal cancer as the most common diagnosis who were not taking opioid analgesics, found that controlled-release oxycodone tablets offer stable and adequate pain control within a short period. Starting with a 5 mg dose every 12 hours, the dose can be effectively titrated. Chest pain and abdominal pain were the most common sites of pain in these patients.
No difference in efficacy has been found between codeine plus paracetamol, tramadol, or hydrocodone plus paracetamol. However, the side effect profile of tramadol was most unfavourable (Rodriguez, 2007).
Morphine, a step III drug when given in low doses in opioid-naive cancer patients, achieves a greater reduction in pain as compared to step II drugs (Caraceni et al, 2012). Codeine, tramadol, and hydrocodone are classed as step II opioid drugs, while oxycodone, morphine, and hydromorphone are step II drugs when used in low doses and step III drugs at high doses.
Step II drugs such as hydrocodone, morphine, and hydromorphone are similar in efficacy and there is no recommendation from WHO regarding which to choose among these drugs when treating moderate-to-severe cancer pain. The factors to be considered when choosing opioid drugs are sufficient availability of the drug at pharmacies, drug profile, comparative adverse effects, comparative analgesic effects, and individual patient factors (Barnett, 2001).
Fentanyl is another important component in the management of cancer pain. In a study population, buprenorphine, administered through a transdermal delivery system, was also shown to be an effective analgesic against chronic, severe pain. Fentanyl, delivered via transdermal therapeutic system, has been used in cancer and chronic pain (Tassinari et al, 2008; Jeal et al, 1997). The low side effect profile of fentanyl delivered via a transdermal route also assists in its increased use. It has been recommended that fentanyl and buprenorphine, through both transdermal and intravenous routes, are the safest opioids for pain management in patients with chronic kidney disease at stage four or five (Fallon et al, 2018).
While initiating opioids in opioid-naive patients, physicians should evaluate any drug interaction of opioids with current medications, and any prior history of exposure to opioids. The starting dose of opioids should be kept as low as possible, to allow the body to tolerate the dose as well as eliciting a reduction in pain. The dose should be adjusted according to the requirement of the patient, in the context of the severity of pain. Oxycodone 5 mg may be combined with paracetamol 325 mg to be administered four times a day. The starting dose of morphine is 10 mg every four hours, with no maximal dose limit (Guidelines on Pain Management and Palliative Care, 2013).
Because of the potential adverse effect of opioids, clinicians should always maintain a balance between dose and efficacy. The titration of opioids is an important concern when the current dose fails to reduce the severity of pain. The reasons for the inefficacy of opioids in cancer pain management are low dose and inadequate frequency. The dose is titrated according to patient response at the current dose. If the drug does not have any impact on pain, a 100% increase in dose is recommended, while a 50% increase is advised in cases when the patient has moderate pain relief with the existing dosage regimen (Goldberg et al, 2013).
Opioids are potent analgesics and maintain a dose-dependency analgesic effect, but their use is generally limited by their side effects. These include constipation, respiratory depression, nausea, sedation, myoclonus, and abdominal pain. Many of these side effects, such as sedation, subside within a few days of administration (Gehdoo, 2006).
No significant improvement was seen in cancer pain relief in patients when opioids were combined with gabapentinoids. However, a benefit with combination therapy in patients with neuropathic pain cannot be excluded (Kane et al, 2018).
Antidepressants
Antidepressants are generally used for managing neuropathic pain. Neuropathic pain may be cancer-generated or chemotherapy-induced. Approximately 20–40% of the cancer patients are affected by neuropathic pain (Bennett et al, 2012).
In patients with neuropathic pain and depression, duloxetine or venlafaxine can be considered, while in the patients with insomnia or anorexia, mirtazapine should be administered (Ahmed, 2019).
Anticonvulsants
Gabapentin and pregabalin have a well-established efficacy in the management of cancer-induced neuropathic pain (Fallon, 2013). Gabapentin has shown efficacy in reducing neuropathic cancer pain in patients already on opioids. The combination of gabapentin and morphine is more effective than either drug alone (Bar, 2010).
Pregabalin is effective in the management of cancer pain and is used at all steps of the WHO analgesic ladder. A 50% rise in the use of opioids was seen in patients when pregabalin was discontinued. Discontinuation was primarily due to feeding habit difficulties, especially in terminally ill cancer patients (Yajima et al, 2016).
Radiation and chemotherapy
Radiation and chemotherapy are used as radical treatments to cure, or palliative treatments for symptomatic control in cancer. These therapies help to relieve pressure from the organs and nerves, through the total ablation of cancer cells or debulking of tumours and thus reduce pain. The effect of radiation therapy may be reported a few weeks after initiation of treatment (Lahoud et al, 2016). However, the side effects of both radiotherapy and chemotherapy may also be the source of pain.
Pain management through special procedures
When the systemic regimen implemented for pain relief is ineffective, alternative procedures should be explored.
The neural blockade blocks the neuronal pain pathway. The nerve to be blocked is subject to the type of cancer; for instance, in terminal stages of head and neck cancer, trigeminal and glossopharyngeal nerves are blocked, while in malignancies of the thoracic region, intercostal nerves are blocked through neurolytic drugs (Gehdoo, 2006). Intercostal nerve blockade imparts a maximum benefit to those patients who do not have sufficient pain control with high-dose morphine (Wong et al, 2007).
A comparison between the early and late use of such interventions has been completed. In a randomised controlled trial, it was shown that implementing such interventions early in the pain management regimen results in a low dose of analgesic and improved quality of life (Amr et al, 2014).
Complementary strategies
Complementary treatments are those used alongside standard medical treatment (National Cancer Institute, 2019). The intensity of cancer pain is increased in cases of mood disturbance, anxiety, depression, and fear (Zaza et al, 2002). Various psychotherapeutic interventions, such as behavioural training, education, and individual psychotherapy, improve distress, anxiety, and quality of life of patients (Mehta et al, 2015)
Behavioural interventions are also useful in pain management in some patients. Yoga, meditation, hypnosis, music therapy and systemic desensitisation are useful as an adjunct pain management strategy (Menefee et al, 2007).
Acupuncture is a traditional Chinese procedure that is a safe and effective adjuvant treatment in the management of symptoms of cancer and side effects of chemotherapy, radiation therapy, surgery and hormonal therapy (Weidong et al, 2008). In a study by Molassiotis and colleagues (2012), 302 breast cancer patients experiencing long-term fatigue were assigned to one of two groups: usual care or acupuncture plus usual care. Acupuncture was done through needling at three points, ST36, SP6, and LI4. The endpoints were measured at six weeks through the Multidimensional Fatigue Inventory. Results show significant improvement in mental fatigue, activity, motivation, anxiety, depression, and quality of life.
Conclusion
The WHO ladder is the base on which the cancer pain management stands. Various alterations to the WHO analgesic ladder can be made, depending upon the severity of pain and the requirement of the patient. Treatment is started with paracetamol and NSAIDs and, later, opioids are added for better pain relief. Systemic treatment is supported by surgical interventions as well as complementary therapies. It should be noted that managing the symptoms of pain in the early stages, through the simultaneous use of various procedures reduces, the long-term burden of pain. Apart from drafting an effective and generalised cancer-pain treatment plan, there is also a need to bring pain management onto the priority list of the clinicians and other related healthcare providers, including paramedical staff. Adjuvant therapies plays an important role in the management of cancer pain and thus, should be included in the WHO approach to pain management.
Key Points
- Pain in cancer is a highly undertreated and under-recognised symptom. Adequate treatment of pain significantly improves the quality of life
- Various barriers including the patient barrier, physician barrier and healthcare system barrier are responsible for the inadequate focus on cancer pain
- Healthcare professionals should adopt a flexible approach, while executing a strategy for pain management.
- The goal of cancer pain management should be to improve the quality of life and to make the physical and psychological health of the patient better
CPD reflective questions
- Do you comprehensively evaluate the barriers that exist before planning a strategy for cancer pain management in particular patients?
- Do you use various strategies for the management of cancer pain? If not, does a single pain management option provides adequate relief to your patients?
- Are you aware that various complementary procedures are available that can help in your endeavour of providing pain-free life to your patients? How would you change your treatment strategies after reading this article?