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Pain is one of the most common and feared symptoms experienced by people with cancer. Poor pain control is associated with changes in lifestyle, functional ability, and personality that have a deleterious effect on quality of life.
In Ireland, the prevalence of cancer continues to rise with an average of 40,000 new cases diagnosed each year. Approximately 150,000 people are currently either living with or have survived a diagnosis of cancer. A recent systematic review and meta-analysis estimates the prevalence of cancer pain at 39 per cent after curative treatment, 55 per cent during anti-cancer treatment and 66 per cent in advanced, metastatic or terminal disease. Of those, 38 per cent reported moderate to severe pain.
Given the increasing cancer prevalence and the number of survivors living to an older age, the clinical burden of cancer pain is significant and effective management at all stages of the illness is essential.
In Ireland, we are fortunate that the long-awaited National Clinical Guideline for the Pharmacological Management of Cancer Pain in Adults was launched in November 2015. This guideline presents 42 evidence-based recommendations that have undergone rigorous scientific assessment with the aim of improving cancer pain and quality of life. Recommendations from this guideline form the basis for the discussion in this article.
Pain in cancer is a complex, subjective, multidimensional experience. It may be caused by the disease itself, cancer treatment or unrelated co-morbidities. To achieve optimal control, it is important to understand the underlying pathophysiological mechanism of each pain. Our understanding of pain mechanisms has improved greatly over the past 20 years. It is now commonly known that physical injury, pain pathways and the emotional processing of this information are interlinked in the nervous system. A feedback system between the brain and spinal cord influences pain input at spinal levels. Anxiety, fear and sleep disturbance, by their effect on the limbic system, may therefore impact the overall experience of pain.
Pain is classified into three broad categories:
1. Nociceptive pain characterised by stimulation of nociceptors; sensory receptors that respond to tissue damage. Two different sub-types exist: Firstly, somatic receptors which are located in the musculoskeletal system and activated by damage to skin, bones, muscles or joints. Secondly, visceral receptors triggered by damage to internal organs. Nociceptive pain usually responds to opioid medication.
2. Neuropathic pain occurs due to damage to the central or peripheral nervous system. It may be associated with altered or absent sensation and is only partially opioid responsive.
3. Mixed pain with components of both nociceptive and neuropathic pain.
Cancer patients may present with either constant background pain requiring regular analgesia or transient breakthrough pain episodes despite stable and adequately controlled background pain.
When it comes to pain management, individuals require a multifaceted approach comprised of pharmacological and non-pharmacological interventions alongside psychosocial strategies. Once a comprehensive assessment (physical, psychosocial and emotional) has been completed, a treatment plan should be formulated.
In 1986, the World Health Organisation (WHO) proposed a strategy for cancer pain management based on a sequential 3-step analgesic ladder. Treatment options escalate from non-opioids to weak opioids to strong opioids according to pain severity. This guideline has been extensively validated and thirty years later remains the mainstay of cancer pain management.
The WHO guideline should be used as a framework to direct analgesic choice and administration. It is not however designed for use in isolation. Alternative modalities such as chemotherapy, radiotherapy, surgery, interventional pain procedures as well as non-drug treatments should also be considered where appropriate. The primary focus of optimal analgesia with a minimum of side-effects can be achieved through a combination of these approaches. Pharmacological intervention still remains key in effective cancer pain management however.
In the presence of background pain, the fundamental principles of the WHO ladder dictate that analgesics should be prescribed by the mouth, by the clock, by the ladder, with individualised dose titration and attention to detail. Pain should be regularly assessed and appropriate medication prescribed according to the ladder. Pain severity should determine the strength of analgesia while analgesic choice is influenced by the cause and type of pain.
Step 1: Mild pain
Non-opioid medications such as paracetamol and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are used to manage mild pain. Paracetamol should be used either alone or in combination with NSAIDs. Numerical score rating is 1 to 2 out of 10.
Step 2: Mild to moderate pain
Codeine, dihydrocodeine and tramadol are weak opioids used in Step 2 of the ladder. Tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, has recently emerged as an alternative on the basis of a more tolerable gastrointestinal profile. The current evidence base however still supports the use of codeine/paracetamol combinations in preference to tramadol or tapentadol.
The usefulness of Step 2 has recently come under debate. It has been suggested that Step 2 (weak) opioids may have a limited role as their use may cause a delay in titration to effective strong opioid with a resulting period of uncontrolled pain. To avoid this, the guideline recommends the selection of appropriate analgesic according to current pain severity. Numerical score rating is 3 to 6 out of 10.
Step 3: Severe pain
Morphine sulphate, oxycodone, hydromorphone, fentanyl and buprenorphine are all examples of Step 3 strong opioids. Opioid choice should take into account efficacy, safety and flexibility of dosing. Morphine sulphate has long been considered the opioid of first choice for the treatment of severe pain. This was predominantly based on extensive clinical experience, as well as a combination of established efficacy and safety data, lower cost and widespread global availability.
Since the publication of the 2nd edition of the WHO guidelines in 1996, the availability and use of other opioids such as oxycodone, hydromorphone and fentanyl has become more commonplace. This has raised questions about the traditional use of morphine sulphate as the first-line Step 3 opioid.
In a recent meta-analysis, Caraceni demonstrated equal efficacy and tolerability of morphine sulphate, oxycodone, hydromorphone and methadone. All of these medications are therefore considered valid choices as first and subsequent choice oral opioids for moderate to severe cancer pain.
Use of methadone is however only recommended under specialist guidance due to its complex pharmacokinetic profile. Methadone is a synthetic preparation with mu-opioid receptor agonist and NMDA receptor channel blocker properties. It is protein bound and lipid soluble with a high volume of distribution. This results in a long and unpredictable half-life causing potential problems with accumulation and toxicity.
Transdermal fentanyl and buprenorphine have also emerged as valuable alternatives in selected patients. They may be particularly relevant in patients with stable pain on an established opioid dose where tablet burden or poor compliance proves a challenge. Due to their complex pharmacokinetics and pharmacodynamics, transdermal opioids are not recommended in those with acute or uncontrolled pain where opioid requirement may be rapidly escalating as therapeutic levels are not usually reached until 12-16 hours after application. Numerical score rating is 7 to 10 out of 10.
Side-effects of opioid medications are common and may compromise their therapeutic benefit. The most commonly experienced adverse effects are those of opioid-induced bowel dysfunction and neurotoxicity.
Opioid-induced bowel dysfunction can cause nausea, vomiting and constipation. Although nausea and vomiting are usually transient and respond to preventative anti-emetics, the development of constipation may prove dose-limiting. Most patients will at least require the prescription of regular laxatives (stimulant ± softener). The use of peripheral opioid receptor antagonists may ultimately need to be considered in minority with treatment refractory constipation.
Opioid induced neurotoxicity is common and may present on a spectrum from mild sedation to delirium. Sedation is usually transient and associated with opioid initiation or titration. The management of delirium proves more challenging however as it is often multifactorial with opioid analgesics contributing to the presentation.
It is essential to anticipate and monitor for side-effects as prompt management can prevent adverse outcomes.
On administration of opioids for cancer pain, it is recognised that a small proportion of people will experience insufficient pain relief, persistent side-effects or a combination of the two despite opioid titration. In this instance, opioid rotation is deemed necessary. This involves the clinical practice of substituting one opioid with another in order to achieve satisfactory pain relief while minimising side-effects. This practice is necessary in 20-to-44 per cent of cancer patients. A variety of conversion tables, including those in the national guideline, are available to guide opioid rotation. These tables are based on relative potency ratios, however it is not an exact science. As these tables act as a rough guide, caution is recommended and regular review advised to avoid under, or over, dosing with related side-effects.
Breakthrough pain is recognised as a transient increase in pain intensity over background pain. Episodes may occur spontaneously or relate to a predictable trigger. Identification of these characteristics guides effective management. Typical features of breakthrough pain include rapid onset, severe intensity and self-limiting duration (less than 30 minutes). Although regular opioids are prescribed for background pain, it is widely recognised that the use of a pharmacological “rescue” or “breakthrough” medication is required for the management of breakthrough pain.
Once the background analgesic dose is optimised, the traditional approach has involved the use of supplemental doses of oral immediate release oral opioids, given before or immediately after the pain has occurred. The dose administered is based on the individual’s background opioid dose and varies from one-tenth to one-sixth depending on the dosing interval used. The typically short-lived duration of breakthrough pain often mean that the pain has resolved before therapeutic levels of this medication have been achieved however.
In recent years, a number of transmucosal fentanyl formulations have been developed specifically to target breakthrough cancer pain. Fentanyl is lipophilic making it suitable for transmucosal administration, either orally or intranasally. The fast onset-offset profile of these agents mirror breakthrough pain characteristics. Given their high potency and rapid onset of action, patients should be carefully selected based on clinical characteristics and established opioid dose. No correlation has been found between the dose of rapid acting fentanyl formulations and the background opioid dose, therefore individual titration is recommended.
In a Cochrane systematic review in 2013, Zepetella concluded that both formulations are effective for breakthrough pain when compared to placebo or oral morphine sulphate. Given a lack of evidence to support the use of one drug over another, it is currently recommended that breakthrough cancer pain is managed with either oral immediate release opioids or transmucosal fentanyl formulations.
Adjuvant analgesics are medications with a primary indication other than pain, but have analgesic properties in certain circumstances. Adjuvant analgesic medication can be usefully added at any stage of the WHO ladder. Their use may be synergistic when prescribed with opioids. This produces better pain control, at lower opioid doses, with fewer side-effects.
Cancer pain is a multidimensional symptom that remains an ongoing challenge for healthcare professionals. Pain control can be achieved by a step-wise pharmacological intervention combined with appropriate adjuvant and non-pharmacological strategies. Successful cancer pain management relies on a systematic yet individualised approach to assessment, intervention, and frequent reassessment of response to treatment while maintaining excellent communication with the patient.