Pain

KEYPOINTS

• Pain in advanced cancer occurs about 70-90% of the time
• Almost all pain can be satisfactorily controlled using simple medication combinations
• The use of the World Health Organization (WHO) analgesic ladder (see WHO Pain Ladder) is a helpful tool in treating pain
• The WHO method can be summarized in five phrases: “by mouth”, “by the clock”, “by the ladder”, “for the individual” and “attention to detail”
• Acetaminophen/paracetamol and NSAIDs can be used for mild pain
• Opioids such as morphine should be used in moderate to severe pain
• Remember to prevent or treat the side effects of morphine such as constipation and nausea/vomiting
• There is no “upper ceiling” dose to the amount of morphine that can be used. The right dose is the dose that works
• Neuropathic pain is common and is pain which is transmitted by a damaged nervous system (see An Approach to Neuropathic Pain)
• Consider the use of adjuvant medications at all levels of the analgesic ladder (especially with neuropathic pain)

• Infants and children experience pain as much as adults and it is common in advanced cancer and in other severe life threatening diseases
• Pain receptors are mature (and inhibitory systems are immature) at birth therefore infants and newborns do feel pain (perhaps even more so than adults)
• Pain that is poorly managed initially can lead to difficult to treat neuropathic pain syndromes and other symptoms
• Pain suffered by children with life limiting disease may have considerable effects on both the child and others

ASSESSMENT

(see Foreword)

• A good clinical assessment is important to try and identify the underlying cause of the pain (e.g. tumour involvement, bone metastases, liver enlargement, etc.)
• Listening to the patient describe their pain location, intensity, quality, “what makes it worse”, “what makes it better”, etc. can tell a lot about what might be causing the pain and how best it might be treated
• The use of pain measurement scales such as the Visual Analogue Scale (VAS) or a “0-10” scale are important tools to use in assessing a patient’s pain and the response to treatment
• The impact of pain on things such as function and sleep is important to ask about
• Investigations to consider may include
  • Radiologic investigations (e.g. x-ray) to determine if there is bony metastasis or tumour involvement
• Assess for the presence of neuropathic pain (see An Approach to Neuropathic Pain)
  • Pain or discomfort resulting from injury to the peripheral or central nervous system
  • Pain is often described as “burning, stabbing or shooting”
  • Allodynia or hyperalgesia may be found on exam and suggests the presence of neuropathic pain
    • Allodynia – something that is usually not painful is now experienced as painful
    • Hyperalgesia – something that is usually a little painful is now experienced as more painful

• A quiet sleeping child may be exhausted and withdrawn but may still be in pain
• Children may fail to report pain because they do not want to be thought of as ‘bad’ or because they fear what might happen next (e.g. they will receive a painful injection)
• Children are good at self distraction and may still be in pain at play or watching TV etc.
• Even small children can “self report” pain
• A number of tools based on age, development and ability to communicate have been developed

MANAGEMENT

• Consider treatment of the underlying cause (e.g. oncological treatment of tumour, radiation for bone metastasis etc.)

Consider if patient is well enough to benefit

• See WHO Pain Ladder
• The WHO method can be summarized in five phrases: “by mouth”, “by the clock”, “by the ladder”, “for the individual” and “attention to detail”

For Mild Pain

• Acetaminophen/paracetamol 650 mg-1 gm every 4h or 1 gm q6h (daily maximum 4 g/d)
  • Hepatotoxicity can occur at doses higher than this
  • Acetaminophen/paracetamol can also be combined with NSAIDs
• Non Steroidal Anti-inflammatory Drugs (NSAIDs)
  • Produce an analgesic effect within 1 to 2 hours
  • Serious side-effects can occur with NSAIDS including:
    • Gastrointestinal (GI bleed)
    • Renal toxicity
    • Congestive heart failure
  • They should therefore be used with caution especially in patients at risk for GI or renal toxicities
  • If GI symptoms occur, the NSAID can be discontinued or the risk of GI toxicity can be reduced by the addition of a protective agent such as an H2 receptor antagonist (e.g. ranitidine, misoprostol or omeprazole)
  • Evidence to support efficacy or safety of one NSAID over another is currently lacking
  • Examples of NSAIDs include:
    • Ibuprofen 200-400 mg tid PO
    • Diclofenac 50 mg tid PO/SC
    • Naproxen 250-500 mg bid PO/PR
    • Ketorolac 10 mg qid PO or 10-30 mg tid SC
    • Multiple other NSAIDs exist

For Moderate Pain

• A “weak” opioid such as codeine 30-60 mg q4h PO or tramadol 50 mg qid PO can be tried. Codeine is often combined with other agents such as acetaminophen/paracetamol and thus maximum doses may be limited by the amount of acetaminophen/paracetamol
• Morphine can also be used at this point and should definitely be used if the pain is not controlled by codeine or other means
• Remember to consider the use of adjuvants along with the opioid

For Severe Pain

• Morphine or another opioid should be started
• The initial starting dose will depend on the patient’s previous exposure to opioids:
  • A dose of morphine 2.5 mg regularly q4h PO (or 1 to 2 mg SC/IV) and a breakthrough or rescue dose every hour, as required (see Breakthrough or Rescue Doses of Morphine) is suitable for an opioid-naive patient
  • A dose of morphine 5-10 mg regularly q4h PO (or 2.5-5 mg q4h SC/IV) and a breakthrough or rescue dose every hour, as required (see Breakthrough or Rescue Doses of Morphine) should be used for patients who have already been on codeine
  • It is necessary over the next days to titrate the regular dose to achieve good control (more than 3 BTDs/day often means that the baseline morphine is not enough)
  • To determine the new dose, add the number of breakthroughs being used in a 24h period to the regular total daily dose. Then divide by 6 to determine the new q4h dose. Alternatively, you can also increase the total daily opioid dose by 25% to 50% depending on the severity of the patient’s pain
  • Remember that there is no “upper ceiling” dose to the amount of morphine that can be used. The right dose is the dose that works
• Alternative routes for morphine include: rectal, subcutaneous, buccal, intravenous and via a gastrostomy tube – the oral route for morphine should be the route of choice in most cases
  • The PO: SC morphine ratio is 2:1
  • The PO: IV morphine ratio is 2-3:1
  • e.g. 10 mg oral morphine = 5 mg SC morphine
• Be aware, educate patients/families about, prevent and treat the common side effects of morphine:
  • Constipation (prescribe laxatives/stool softeners when starting someone on morphine; see Constipation)
  • Nausea (usually only temporary - ensure an antiemetic is available especially if just starting someone on morphine)
  • Excessive sedation or drowsiness (usually only temporary)

Adjuvants

• Adjuvants are medications or measures that provide relief to the patient in addition to the analgesic medications themselves
• They are often used in pain due to bone metastases PO and in neuropathic pain
• For bone pain consider:
  • NSAIDs, corticosteroids, radiotherapy
• For neuropathic pain consider (see An Approach to Neuropathic Pain):
  • Trial of antidepressant: start with low dose and increase every 3-5 days if tolerated (eg, nortriptyline, amitriptyline or desipramine 10-150 mg PO once daily) and/or
  • Trial of anticonvulsant: start with low dose and increase every 3-5 days if (e.g. gabapentin 100-200 mg tid PO; carbamazepine100-400 mg bid PO)

• Opioids are the main analgesics for children with severe life threatening disease
• Use WHO Pain Ladder (including the use of adjuvants) as in adults
• Acetaminophen/paracetamol
  • Under 1 year: 10-15 mg/kg q4h/prn PO
  • 1-5 years: 120-250 mg q4h PO
  • 5-12 years: 250-500 mg q4h PO (maximum of 75 mg/kg/day)
• Diclofenac##
  • 6 months to 12 years: 2-3 mg/kg/24h in divided doses bid or tid PO
• Naproxen 5-7 mg/kg q12h PO
• Ibuprofen 5-10 mg/kg q8-12h PO
• Ketorolac 0.2 mg/kg q4-6h PO, 0.2-0.5 mg/kg q 6h IV prn
• Amitriptyline 500 mcg/kg HS
• Gabapentin starting at **10-15 mg/kg/24 hrs in divided doses bid or tid (max of 60 mg/kg/24hrs)
• Codeine
  • Children more than 6 months: 0.5-1.0 mg/kg q4h PO (max 60 mg/dose)
  • See comment under Pitfalls
• Morphine
  • Starting doses for opioid naïve infants less than 6 months: 0.01 mg/kg q4h SC/IV or 0.02 mg/kg q4h PO
  • Starting dose for opioid naïve infants/children more than 6 months: 0.02 mg/kg q4h SC/IV or 0.04 mg/kg q4h PO
• Carbamazepine
  • Less than 6 years: 10-20 mg/kg/24h in divided doses bid or tid PO
  • Over 6 years: 100 mg once daily PO

PITFALLS/CONCERNS

• Pethidine/meperidine if used on an ongoing basis will cause a buildup of the metabolite (normeperidine) and may cause delirium and seizures – it should be avoided in the treatment of cancer pain
• Never ever use a slow-release opioid as the breakthrough or rescue medication (use regular short-acting instead)
• Serious side-effects can occur with NSAIDs – they should be used cautiously. An opioid such as morphine may be a more effective and safer option

• Children less than 6 months are more sensitive to possible opioid induced respiratory depression and therefore need lower initial doses with subsequent normal titration
• Because of some immature metabolic processes codeine may not be appropriate in younger children and infants
• About 10-15% of adults and up to 35% of children may not be able to metabolize codeine and therefore it may not be an effective analgesic
• Urinary retention and pruritus (as a side effect of opioids) are more commonly seen in children compared to adults

PALLIATIVE TIPS

• Treat pain promptly and aggressively!!!
• The WHO guidelines remind us that the "relief of psychological, social and spiritual problems is paramount". Attempting to relieve pain without addressing the patient’s non-physical concerns is likely to lead to frustration and failure
• Constant pain requires regular analgesia. Use “around-the-clock” dosing to treat and prevent pain
• Make sure to provide a breakthrough or rescue dose (BTD) in addition to the regular dose of morphine
• Optimize the opioid by titrating up until pain improved
• The PO morphine to SC/IV morphine ratio is 2:1, e.g. 10 mg oral = 5 mg SC
• Morphine 10 mg PO = codeine 100 mg PO
• Remember the use of adjuvants in the treatment of pain (e.g. neuropathic pain - see An Approach to Neuropathic Pain)

• Children have less distress when they can understand what is happening and are involved in their symptom management
• Play, music and games can be very helpful in association with the pharmacological methods as described above

SOURCES/REFERENCES

1. Downing GM, Wainwright W, editors. Medical care of the dying. 4th ed. Victoria (BC): Victoria Hospice Society; 2006.
2. Marinangeli F, Ciccozzi A, Leonardis M, Aloisio L, Mazzei A, Paladini A et al. Use of strong opioids in advanced cancer pain: a randomized trial. J Pain Symptom Manage 2004;27(5):409-416. http://www.ncbi.nlm.nih.gov/pubmed/15120769
3. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev 2005(1):CD005180. http://www.ncbi.nlm.nih.gov/pubmed/15654708
4. National Comprehensive Cancer Network. Clinical practice guidelines in oncology [Online]. Available from: URL:http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
5. Wiffen PJ, Edwards JE, Barden J, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev 2003(4):CD003868. http://www.ncbi.nlm.nih.gov/pubmed/17943804
6. William DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. Br J Anaesth 2001;86(3):413–421. http://bja.oxfordjournals.org/cgi/reprint/86/3/413
7. World Health Organization. Cancer pain relief. 2nd ed. Geneva: World Health Organization; 1996. [Online]. Available from: URL:http://www.painpolicy.wisc.edu/publicat/cprguid.htm
8. World Health Organization. Technical report #804. Cancer pain relief and palliative care. Geneva: World Health Organization; 1990.
9. World Health Organization. Cancer Pain Release 2006;19(1). [Online]. Available from: URL:https://whocancerpain.bcg.wisc.edu/index?q=node/15
10. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 1995;63(1):65-76. http://www.ncbi.nlm.nih.gov/pubmed/8577492

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