World Health Organization Pharmacologic Treatment

4. By the child: treatment plans should be indi- vidualized to the child’s pain level and response to therapy. For mild pain step 1, a nonopioid analgesic should be primarily utilized. Ibuprofen and acet- aminophen have been established for analgesia in children 3 months of age; newborn trials have found these agents to be ineffective Berde and Sethna 2002 . Although not evidence-based, non- steroidal anti-infl ammatory drugs NSAIDs are generally avoided in pediatric oncology patients due to reversible antiplatelet and fever-masking effects. Step 2 in the WHO pain ladder calls for weak opioid therapy with the consideration of adjuvants such as combined opioid-NSAIDs. Step 2 has not been well characterized and calls for the use of pain medications that are controversial in pediat- rics Tremlett et al. 2010 . Codeine, for example, should be avoided in children due to concerns for both effi cacy and safety. Genetic variability in cytochrome P450 isoenzyme 2D6 CYP2D6 sig- nifi cantly alters the ability to metabolize the drug into its active metabolite, morphine. Roughly one-third of Caucasian children have limited ability or are unable to metabolize codeine to morphine, and codeine-related deaths have been reported in children with CYP2D6 alleles associ- ated with ultrarapid metabolism Williams et al. 2002 ; Kelly et al. 2012 ; Anderson 2013 . The lat- ter has led to a Food and Drug Administration FDA black box warning which advises that codeine is contraindicated in children after adenotonsillectomy for obstructive sleep apnea Kuehn 2013 . Additionally, medications such as tramadol have not been well studied in pedi- atrics, have a number of drug-drug interactions and reach a ceiling analgesic effect Zernikow et al. 2009 . Fixed combination products, such as acetaminophenoxycodone and acetaminophen hydrocodone, cause diffi culty in dose escalation of the opioid due to dose limitations from the nonopioid component. Step 3 in the WHO pain ladder calls for opioid therapy with consideration of an adjuvant. Several studies have demonstrated the effi cacy of opioids in pain treatment. Although adjuvant therapy can be considered for the treatment of certain types of pain, a prospective non-randomized study in pediatric oncology patients demonstrated little additional analgesic benefi t from the addition of nonopioids in children already receiving opioids Zernikow et al. 2006 . Further, analgesia was not improved when NSAIDs were added to a standing regimen of opioids, and the benefi t of NSAIDs given for 7 days has not been established McNicol et al. 2005 . Lastly, children with can- cer are at increased risk of NSAID-related bleed- ing as well as renal and gastrointestinal toxicity due to concurrent use of medications required for treatment of their tumors.

9.4.2 Intermittent Opioid Use

In opioid-naïve pediatric oncology patients, it is important to start with short-acting opioids to control acute, moderate to severe pain. Long- acting opioids should not be used for acute pain as they are designed to slowly release medication over a long period of time, generally 12 h. In chil- dren it is important to choose the type, prepara- tion, dose and route of opioid such that the patient can comply with therapy. For example, intramus- cular doses are avoided due to pain associated with administration and bleeding risks in patients with coagulopathy. Dosing depends on the route of administration, which in turn dictates the time to onset of medication effect. Rectal, sublingual and oral dosing are equivalent and have maximal 3 2 1 Opioid for moderate to severe pain ± non-opioid ± adjuvant Opioid for mild to moderate pain ± non-opioid ± adjuvant Non-opioid for mild pain ± adjuvant Fig. 9.2 World Health Organization three-step pain ladder S. Malhotra and S. Maurer analgesic onset within 30–45 min. Subcutaneous, intramuscular and intravenous IV dosing are also equivalent, but the onset of action is faster, typically within 15 min Mercadante 2012 . When switching between oral and IV routes, dos- ing must be adjusted using a standardized equi- analgesia table Table 9.2 . It is important to remind patients changing from IV to oral dosing that while the analgesic effect is expected to be similar between routes, the time to onset of anal- gesia is not. Short-acting doses are given as needed until a clear sense of the total daily opioid dose required to keep the patient comfortable is established. Once stable daily needs are determined and the need for pain medication is expected to persist, long- acting doses should be considered. Unless there are contraindications such as renal failure, morphine is generally used as the fi rst-line opi- oid. Initial doses should be calculated using a dose-per- kilogram basis Table 9.3 . Doses should be increased by 25–30 for uncon- trolled pain. Case 1: Initiating Opioid Therapy A 10-year-old, 30 kg boy presents to your outpa- tient clinic with a 3-month history of progressive right hip and knee pain. CT scan shows a pelvic lesion concerning for Ewing sarcoma, and now you and the family are planning an outpatient work-up of his tumor prior to starting therapy. The mother reports that he has been using fi ve doses a day of acetaminophen for pain relief. Eric says he feels like he’s being “stabbed in the leg” and rates his pain as 8 of 10 with little relief from the acetaminophen. He has no drug allergies. They are asking if he can try something else for pain relief. Plan Looking at the WHO pain ladder, you decide to move up to opioids for moderate pain. Since he will be outpatient, you decide on an oral route, noting the patient prefers tablets to liquid medi- cations. You decide to start with immediate- release morphine at a dose of 0.2–0.3 mgkg every 3 h as needed Table 9.3 . 30 0 2 0 3 6 9 kg mg po morphine kg mg po morphine × − = − . . You note that the smallest tablet preparation of immediate-release morphine is 15 mg, so you instruct him to take 7.5 mg 0.5 tab every 3 h as needed and to call if it is ineffective. Of note, prep- arations including hydrocodone rather than oral morphine would also be reasonable in this case.

9.4.3 Long-Acting Opioids

One should consider the use of long-acting opi- oids when a stable daily dose of opioids is achieved and a persistent use of pain medication is expected. As described above, long-acting agents should not be used for acute pain as they slowly release medication. Long-acting opioids allow for around-the-clock analgesia and are used in combination with short acting opioids that serve to manage acute or breakthrough epi- sodes of pain. The benefi ts of long-acting opioids include less use of breakthrough medication, improved sleep at night, improved comfort upon waking from sleep and less drowsiness. When determining the amount of long-acting opioids, it is important to calculate the previous day’s total opioid requirement oral morphine equivalent or OME. Long-acting opioids should be dosed at 12 to 23 of the total OME. Slow- release morphine is used as fi rst-line treatment and generally prescribed every 8–12 h. Doses should be reevaluated and titrated upwards if optimal pain control is not reached. This often occurs with disease progression or, less often, as a result of opioid tolerance. Table 9.2 Opioid equianalgesia conversions Medication Parenteral mg Oral mg Morphine 10 30 Oxycodone – 20 Hydromorphone 1.5 7.5 Oxymorphone 1 10 Fentanyl 0.1 a – Adapted from Friedrichsdorf and Kang 2007 ; McGhee et al. 2011 a This dosing is not equivalent for transdermal fentanyl patches. Please refer to the specifi c drug information sheet from the manufacturer for fentanyl transdermal patch equivalency.