Pain control is an integral component of paediatric palliative care. Uncontrolled pain can have significant negative effects, both physically and psychologically in children with cancer. Controlling pain through a variety of modalities reduces this fear.^1,2

Barriers exist in the recognition and management of pain in children. Often children do not verbalise their pain; they may continue to sleep or play in the presence of significant pain or they may be too young to articulate it. In addition, parents and healthcare professionals may have concerns about the use of opioid analgesia. Concerns about adverse effects, addiction and lack of experience in the use of strong opioids all act as barriers in effective pain management in children.^1,2

By educating healthcare professionals and parents on effective methods to lessen the pain, children can achieve improved pain control, improved psychological outcomes and increase their chances for successful cancer treatment. 

Assessment

Thorough assessment is essential, both in understanding the cause of cancer pain and subsequently guiding pain management. The initial pain assessment includes a detailed pain history, including a collateral history from parents or primary caregivers. Caregivers often act as the primary sources of information, especially for preverbal children, as they best know the child’s behaviour. Young children and those with communication difficulties may only show pain through facial expression, behavioural changes or through fear and anxiety. Children can use different sounds or vocabulary to express pain and it is important to establish an understanding of these with the family.³ Children may deny pain due to fear of further painful experiences, eg. further tests/investigations. More than one pain may be experienced at any given time; each needs individual assessment and tailored management.

Evaluation of the impact of pain on the child’s physical activities, on schooling and on their sleep, can be used to gauge pain severity and act as a useful marker for treatment response. 

The use of age-appropriate pain measurement tools can be helpful in both assessing pain severity and its response to different treatment modalities.²

Self-reporting pain measurement tools can be helpful in children of certain ages; visual analogue scales, such as the Wong-Baker Faces scale and the Faces Pain Scale-Revised, are useful for 4-12 year olds, and quantitative visual analogue scales, such as the numerical rating scale (0-10, 10 being the worst pain), are useful in 11-18 year olds. Follow-up pain assessments are needed to evaluate the effectiveness of different treatments/pain interventions used.

Non-pharmacological approach to pain

Pain is a complex multidimensional experience. In addition to a pharmacological approach to pain, psychological and non-pharmacological approaches to treatment are beneficial.^2,4 These include the use of massage, aromatherapy, music therapy, and play therapy. A recent study, although small, shows an improvement in pain scores in children after massage.⁵ The physiotherapist and occupational therapist can provide useful pain control management through use of TENS, splints, manipulation and appropriate aids. 

Pharmacological approach to pain

WHO two-step ladder (for cancer pain in children)

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The WHO Analgesic Ladder for cancer pain was developed in the 1980s. This framework forms the guideline for an approach to cancer pain management for both adult and children. In 2012, this was revised by the WHO from a three-step to a two-step approach for pain management in children with persisting pain, including children with cancer pain. Key points include:

• By the ladder: The two-step analgesic ladder provides a rational simple stepwise approach. The level at which the child enters is determined by the intensity of the pain
• By the clock: Regular scheduling of medications in addition to as-needed dosing (prn) ensures steady blood concentrations
• By mouth: Where possible give medications by least invasive route for children, usually by mouth or buccally 
• By the child: Individualised response to treatment
• Adjuvant analgesia can be initiated at any step of the ladder.

Analgesic doses should be checked with local prescribing guidelines. The UK Association of Paediatric Palliative Medicine (www.appm.org.uk) handbook is a useful guide to analgesic and drug dosing in children with cancer and other life-limiting illnesses. 

Step 1: For mild pain

Paracetamol and non-steroidal anti-inflammatories (NSAIDs) are common step 1 analgesics used in children with cancer pain. Both have analgesic and anti-pyretic properties. Depending on concomitant chemotherapy, use of these agents may be inappropriate. Codeine, a weak opioid that was previously included in the second step WHO analgesic ladder, is no longer recommended. The main concern lies with ultra-rapid metabolisers of codeine who can develop life-threatening respiratory depression.²

Step 2: For moderate to severe cancer pain

Morphine sulphate is recommended as the first-line opioid in treating moderate to severe cancer pain.³ This naturally occurring opiate acts at the mu-opioid receptors. It is metabolised in the liver and its metabolites are excreted renally. In infants up to six months, the half-life is increased and urinary clearance reduced and so dosing intervals are adjusted accordingly, ie. longer dosing intervals.

Morphine sulphate

Morphine sulphate can be administered orally, subcutaneously, intravenously or via epidural or intrathecal route. As with all strong opioids, the oral preparation comes as both a short-acting/immediate-release preparation and a long-acting/slow-release preparation. A liquid immediate-release preparation can be used via an NG tube and so has a role in the neonate. Its onset of action is 20-30 minutes, peak action at 60-90 minutes, and duration of action is 3-6 hours.

Points to remember in the use of morphine sulphate (also applicable to oxycodone and hydromorphone):

• When initiating an opioid in an opioid-naïve child, morphine sulphate is the first-line opioid of choice. Give the short-acting opioid every six hours (q6h) for the first 24-48 hours
• Always prescribe the same dose of short-acting opioid as an  ‘as required’ (prn)/breakthrough dose, with a shorter time interval usually four-hourly, eg. short-acting morphine 2mg every six hours and 2mg as required up to four-hourly 
• After a minimum of 48 hours, the short-acting opioid requirements for the 24-hour period can be calculated and the 12-hourly/BD dose long-acting opioid prescribed. Tablet preparations cannot be crushed or chewed and, therefore, may be unsuitable in some children. Long-acting morphine sulphate is also available in powdered sachet preparations
• When prescribing a long-acting opioid, also prescribe a short-acting opioid from the same family .The prn or breakthrough dosing is 1/6th of the total 24-hour long-acting opioid dose when established on regular long-acting opioid
• The background opioid dose should be increased according to need and is guided by breakthrough doses required
• Oral opioid to subcutaneous opioid ratio is 2:1, ie. morphine sulphate 10mg PO is equal to morphine sulphate 5mg SC or IV.

Opioids should be prescribed with reference to local prescribing guidelines and are usually based on body weight, age and medical conditions of the child (mg/kg body weight).

Oxycodone and hydromorphone are strong opioids with similar pharmacokinetics to morphine sulphate. These are not usually first-line strong opioids but useful in opioid rotation. Opioid rotation is used when intolerable side-effects develop to one opioid and another has to be used to maintain analgesia. Most common indication for opioid rotation in children is excessive side-effects with adequate analgesia (70%) or excessive side-effects with inadequate analgesia (16.7%).⁷

Fentanyl

Fentanyl is a synthetic opioid that is highly lipophilic and acts as a mu-agonist. It is 100 times more potent than morphine. It comes in different formulations, mainly parenteral, transdermal, buccal and intranasal. It is safer in renal failure and is often used when adverse effects of other opioids become dose limiting. Although a small study, there is evidence that the use of transdermal fentanyl is feasible and well tolerated in children and that its pharmacokinetic profile is similar to those for adults.⁸

Its transdermal (TD) preparation could be of use in stable cancer pain when medication burden may be an issue. It is changed every 72 hours, the lowest dose being 12mcg/hour patch. Its peak plasma concentration is 16-24 hours after application. When converting from a slow-release opioid preparation to transdermal fentanyl, apply the patch at the same time as administering last dose of slow-release opioid. Breakthrough doses may be required until the fentanyl reaches steady state. Inter-individual variations in the oral morphine equivalent for transdermal fentanyl exist but guidelines aid in prescribing, eg. TD fentanyl 12mcg/hour is approximately 45mg oral morphine sulphate.²

Methadone

Methadone is a synthetic opioid and N-methyl-D-aspartate (NMDA) antagonist that is available as a liquid. It has a hugely variable clearance so toxicity can occur unexpectedly, requiring careful dosing and monitoring under specialist supervision. It is reported to have advantages in neuropathic pain.^2,4,9

Buprenorphine

Buprenorphine is a partial mu-agonist with effects similar to morphine. It is available as a transdermal preparation and may have less constipation than other opioids.^2,4,9

Conversion ratios 

When switching opioids, a conversion ratio is needed. It is both good and safe practice to return to the 24-hour oral morphine equivalent (OME) dose before proceeding with conversion. Recent European Association of Palliative Care (EAPC) guidelines advised on the following conversion ratios based on evidence to date. Most were from studies in the adult population.¹⁰

• Oral morphine: Oral oxycodone  1.5-2:1 
• Oral morphine: Oral hydromorphone  5:1 

When switching from one opioid to another, advice should be sought from an appropriate specialist.

Side-effects of opioids

Opioids commonly cause side effects and children often do not voluntarily report them. It is important to ask specifically about any possible side-effects so they can be managed and their burden reduced (see Table 1). In some cases, rotation to another opioid to overcome intolerable side effects may be warranted.

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Opioid toxicity

Opioid toxicity can present in a spectrum of symptoms and signs including drowsiness, confusion, visual hallucinations and myoclonus. Respiratory depression is a much feared albeit extremely rare occurrence in cancer pain management. Management involves identification of the cause(s) for toxicity, (eg. infections, metabolic disturbance, and analgesic effect of radiotherapy), address any potential reversible causes, and adjust the opioid – either dose or class of opioid. 

Use of syringe drivers

The preferred route of opioid administration is via the oral route. In certain situations, the oral route may not be optimal, eg. pain crisis, end of life. To maintain analgesia, the intravenous route is preferred in the hospital setting. In the community setting, especially at end of life, the subcutaneous administration of opioids using a syringe driver is more commonly used. 

Many children with cancer have central venous access devices (CVADs) and analgesia can be maintained using this route. However, familiarity in the use of CVADs varies with community healthcare providers. The HSE recently issued guidelines on the use of CVADs in children in the community, which will hopefully encourage their use over the subcutaneous route at end of life.¹¹

Adjuvant analgesia

Adjuvant analgesics include a wide variety of medications that were initially developed to treat other problems but have analgesic properties. These are of particular importance in the management of neuropathic pain. 

When choosing an adjuvant analgesic it is important to consider the effect and side-effects of medications. Some medication side-effects may be helpful in symptom management, eg. amitriptyline for neuropathic pain may also help with hypersalivation. 

It is important to explain the slow onset of action of these drugs and the side-effects to expect. Dose titration should continue until analgesic effect or side effects intolerable.

Anticonvulsants

Anticonvulsants, (eg. gabapentin) are helpful in treating neuropathic pain. Both carbamazepine and gabapentin have been studied in randomised control trials for treating neuropathic pain in the adult population. 

Antidepressants

Antidepressants have a role in treating neuropathic pain. Evidence from adult data supports the use of amitriptyline, a tricyclic antidepressant, in neuropathic non-malignant pain. Although an off-license use, clinical experience demonstrates its usefulness in cancer-related neuropathic pain in both adults and children.

Steroids

Steroids can be beneficial as an adjuvant analgesic agent in managing inflammatory-mediated pain or pain syndromes mediated by peritumoural oedema, eg. headache in raised intra-cranial pressure, neuropathic pain secondary to nerve root compression or spinal cord compression, and pain for liver capsular distension.

Other adjuvants

Radiotherapy can be useful in treating bone pain due to localised metastatic malignant disease. Interventional anaesthesia should be considered in some cases, especially localised neuropathic pain. Examples include epidural, spinal or intrathecal anaesthesia and nerve blocks. Referral to a specialist paediatric pain team is required.

Conclusion

Cancer pain management in children requires a multidisciplinary approach. Following thorough assessment, an integrative approach of pharmacological and non-pharmacological modalities achieves optimal results. The WHO Analgesic Ladder provides a stepwise approach to cancer pain. Resources are available on-line regarding paediatric drug dosing, as mentioned above. Analgesic advice can also be sought from paediatric pain teams and palliative medicine colleagues when needed.

References

1. Geneva, World Health Organisation 1986; Cancer pain relief and palliative care in Children
2. Geneva, World Health Organisation 2012; Guidelines on the pharmacological treatment of persisting pain in children with medical illnesses
3. The Rainbows Children’s Hospice Guidelines: Basic symptom control in paediatric palliative care, 2011
4. Batalha LM, Mota AA. Massage in children with cancer: Effectiveness of a protocol. J Pediatr 2013; pii: S0021-7557 (13) 00165-4. [Epub ahead of print]
5. Collins JJ. Cancer pain management in children. Eur J Pain 2001; 5 Suppl A: 37-41
6. The Association of Paediatric Palliative Medicine, Master Formulary, 2012
7. Drake R, Longworth J, Collins JJ. Opioid rotation in children with cancer. J Palliat Med 2004; 7(3): 419-422
8. Collins JJ, Dunkel IJ, Gupta SK. Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 1999; 134(3): 319-323
9. Zernikow B, Michel E, Craig F, Anderson BJ. Paediatric palliative care: Use of opioids for the management of pain. Paediatric Drugs 2009; 11(2): 129
10. Caraceni A, Hanks G, Kaasa S,et al. Use of opioid analgesics in the treatment of cancer pain: Evidence-based recommendations from the EAPC. Lancet Oncology 2012; 13: e58-68
11. HSE Guidelines 2012. Guidelines for the Care and Management of Central Venous Access Devices when used for a Child in the Community.