Pain prevalence ranges from 33% in patients after curative treatment, to 59% in patients on anticancer treatment, and to 64% in patients with metastatic, advanced or terminal disease.
Despite guidelines and the availability of opioids, undertreatment is common: these data reinforce the recommendation that patients with advanced or metastatic cancer require management within an integrated system for palliative care.

The following is a summary of the recommendations for the management of cancer pain in adult patients.

Assessment
• Intensity of pain and treatment outcomes should be assessed regularly and consistently. The most frequently used standardized scales are the visual analogue scale, the verbal rating scale, and the numerical rating scale.
• Observation of pain-related behaviors and discomfort (facial expression, body movements, verbalization or vocalizations, changes in interpersonal interactions, changes in routine activity) is an alternative to assess the presence of pain in patients with cognitive impairment.
• All components of suffering should be considered and evaluated.

Pain management
• Patients should be informed about pain and its management and should be encouraged to take an active role in their symptom control. Patient education should include information on the appropriate use of opioids and other analgesics, and non-pharmacological approaches.
• The start of pain should be prevented by means of around-the-clock administration, considering the half-life, bioavailability, and duration of action of different drugs.
• Analgesics for chronic pain should be prescribed on a regular basis and not “as required.”
• The oral administration of analgesic drugs should be promoted as the first choice, as this prescribed treatment could be done simply by patients and families.

Treatment of mild pain
• Analgesic treatment should start with drugs appropriate for the severity of pain, as indicated by the WHO analgesic ladder.
• There is no significant evidence to support or refute the use of paracetamol alone or in combination with opioids for mild to moderate pain.
• There is no significant evidence to support or refute the use of NSAIDs alone or in combination with opioids for mild to moderate pain.
• Dipyrone is a non-opioid analgesic that could be used for the treatment of cancer pain, alone or in combination with opioids.

Treatment of mild to moderate pain
• Weak opioids such as tramadol, dihydrocodeine, and codeine can be given in combination with non-opioid analgesics.
• As an alternative to weak opioids, low doses of strong opioids could be an option; this is not included in the WHO guideline.
• There is no evidence of increase in adverse effects from the use of low-dose strong opioids instead of the standard step 2 approach with weak opioids.

Notes
Step 2 of the WHO analgesic ladder has several controversial aspects.
1) Absence of a definitive proof of efficacy of weak opioids
2) The difference in the effectiveness of the drugs between Steps 1 and 2 cannot be demonstrated
3) The effectiveness of Step 2 has a time limit of 30 to 40 days for most patients and the shift to Step 3 is mainly due to insufficient analgesia, and “ceiling effect” with weak opioids, rather than to adverse effects.
4) Many authors propose the abolition of Step 2 of the WHO analgesic ladder, in favor of the early use of morphine at low doses; this is not included in the WHO guideline.

Treatment of moderate to severe pain
Strong opioids are the mainstay of analgesic therapy in treating moderate to severe cancer-related pain.

• The opioid of first choice for moderate to severe cancer pain is oral morphine.
• The average relative potency ratio of oral to intravenous morphine is between 1:2 and 1:3.
• The average relative potency ratio of oral to subcutaneous morphine is between 1:2 and 1:3.
• Fentanyl and buprenorphine (the transdermal or intravenous route) are the safest opioids in patients with chronic kidney disease stages 4 or 5.
• A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid side effects.
• The subcutaneous route is simple and effective for the administration of morphine, diamorphine, and hydromorphone, and it should be the first-choice alternative route for patients unable to receive opioids by oral or transdermal route.
• Intravenous infusion should be considered when subcutaneous administration is contraindicated (peripheral edema, coagulation disorders, poor peripheral circulation, need for high volumes and doses).
• Intravenous administration is an option for opioid titration when rapid pain control is needed.

Scheduling and titration
• Individual titration, e.g., normal-release morphine administered every 4 h plus rescue doses (up to hourly) is recommended for breakthrough cancer pain.
• Immediate and slow-release oral morphine formulations can be used to titrate the dose. Titration schemes for both types of formulation should be supplemented with immediate-release oral opioids, prescribed as required for breakthrough cancer pain.
• The regular dose of slow-release opioids can be adjusted to take into account the total amount of rescue morphine.

Management of opioid side effects
• Laxatives must be routinely prescribed for both the prophylaxis and the management of opioid-induced constipation.
• The use of naloxone (in association with oxycodone) or methylnaltrexone to control opioid-induced constipation may be considered.
• Naloxegol has been shown to be highly effective in opioid-induced constipation, but there is no specific reported experience in the cancer population.
• Metoclopramide and anti-dopaminergic drugs should be recommended for treatment of opioid-related nausea/vomiting.
• Psychostimulants (e.g., methylphenidate) to treat opioid-induced sedation are only advised when other treatment methods have been tried.
• Mu receptor antagonists (e.g., naloxone) must be used promptly in the treatment of opioid-induced respiratory depression.

Breakthrough cancer pain
• Immediate-release opioids should be used to treat breakthrough cancer pain that is opioid-responsive and for which background cancer pain management has been optimized.
• Transmucosal fentanyl formulations (oral, buccal, sublingual, and intranasal) have a role in unpredictable and rapid-onset breakthrough cancer pain.
• There are indications for standard normal-release oral opioids (e.g., morphine) that include a slow-onset breakthrough cancer pain or a pre-emptive administration of oral opioids ∼30 minutes before a predictable breakthrough triggered by known events.

Cancer-related neuropathic pain
• Cancer-related neuropathic pain can be treated using opioid combination therapies and carefully dosed adjuvants, when opioids alone provide insufficient pain relief.
• Patients with neuropathic pain should be given either a tricyclic antidepressant or an anticonvulsant and be monitored for side effects.
• Gabapentin, pregabalin, duloxetine, and tricyclic antidepressant (doses ≤ 75 mg/day) are strongly recommended as single agents for neuropathic pain first-line treatment.
• Interventional treatments of neuropathic pain are based on weak or inconclusive evidence, and should be restricted to patients with neuropathic pain syndromes other than those related to cancer.
• There is a lack of evidence to support the routine use of ketamine in cancer neuropathic pain.

See reference for more information, relative analgesic ratios for opioid switching, intravenous titration, and assessment/treatment algorithms.

This information is from studies in high income country countries, but it may be also useful for countries in other socioeconomic levels.

Adapted from Fallon et al. Clinical Practice Guidelines Annals of Oncology 2018; 29(Suppl. 4). Internet. Available at https://academic.oup.com/annonc/article/29/Supplement_4/iv166/5046945. Accessed on January 27, 2020.