Changing Therapeutics in the Management of Intractable Pain in Children at the End of Life 19952005

Pain that cannot be alleviated using conventional treatment is intractable. Intractable pain that does not respond to therapies beyond conventional practice is refractory. The relief of refractory pain may require a therapy that reduces conscious awareness. Intractable pain in childhood is unusual and is mostly seen in the setting of cancer pain and at the end of life. Intractable childhood cancer pain is usually disease related. Disease-related pain often recurs at the time of tumor recurrence and when the cancer becomes unresponsive to treatment.

A retrospective study published in 1995 examined the opioid requirements of children with terminal malignancy (27). Twelve (6%) of the patients in this study required therapies beyond conventional pediatric opioid dosing. The majority of the patients had neuropathic pain related to tumor location as the basis of their intractability. Eleven patients had spinal cord compression, solid tumor metastatic to the spinal nerve roots, nerve plexus, or large peripheral nerves. Of the patients, 50% had adequate analgesia with either regional anesthesia or high-dose opioid infusion alone. The remaining patients required the prescription of sedation to control refractory pain.

Since the publication of that report, practice has become more sophisticated, with greater understanding of the management of the pediatric pain crisis, the calculation of opioid "rescue" dosing and dose escalation, and opioid switching;

greater understanding of the management of opioid side effects to permit greater opioid dose escalation; the N-methyl-D-aspartate (NMDA) antagonists as new therapeutic options; and better understanding of invasive approaches to pain management in children. Given the change in therapeutics, it may be that fewer children need to be sedated to reduce conscious awareness of intractable symptoms.

4.5.1. The Pediatric Pain Crisis

The pain crisis in a dying child is an emergency and may require treatments beyond conventional means. A specific diagnosis must be made as therapies directed at the primary cause may be more effective in the longer term. The management of intractable pain requires the clinician to be at the patient's bedside to titrate incremental intravenous opioid doses every 10-15 minutes until effective analgesia has been achieved. The analgesic effect of opioids increases in a log linear function, with incremental opioid dosing required until either analgesia is achieved or somnolence occurs (50).

The total amount of opioid administered to achieve this reduction in pain intensity is considered the opioid loading dose. A continuous infusion of opioid may need to be commenced to maintain this level of analgesia, along with "breakthrough" or "rescue" doses. In such circumstances, the initial infusion rate is often based on the opioid administered as a loading dose rather than the "usual" starting doses typically referred to in practical reference manuals (50). An alternative to a continuous infusion of opioid is intermittent parenteral opioid, especially in the setting of an unpredictable pain syndrome.

4.5.2. Rescues

Breakthrough doses (or rescues) are additional doses of opioid incorporated into the analgesic regime to allow for additional analgesia if required by the patient. Breakthrough doses of opioid may be calculated as approx 5-10% of the total daily opioid requirement and may be administered orally every hour (50). Given the frequency with which additional analgesia may be required for severe pain, it may be convenient for some children to self-administer breakthrough opioid doses using a PCA device. Data suggest that 7-year-old children of normal intelligence can use PCA effectively to provide analgesia postoperatively (51).

4.5.3. Opioid Dose Escalation

If pain can be controlled by the opioid loading technique, then the subsequent opioid dose escalation may be calculated as follows:

1. If more than approximately four to six breakthrough doses of opioid are required in a 24-hour period, then the hourly average of this total daily rescue opioid should be added to the baseline opioid infusion. An alternative would be to increase the baseline infusion by 50% (50).

2. Breakthrough doses are kept as a proportion of the baseline opioid infusion rate and, with dose titration, are recalculated as between 50 and 200% of the hourly basal infusion rate (50).

4.5.4. Opioid Switching

The usual indication for switching to an alternative opioid is dose-limiting opioid side effects preventing opioid dose escalation. In the setting of intractability, opioid dose escalation may be limited by opioid-related side effects. An observation is that a switch from one opioid to another is often accompanied by change in the balance between analgesia and side effects (52). A favorable change in opioid analgesia to side effect profile will be experienced if there is less cross tolerance at the opioid receptors mediating analgesia than at those mediating adverse effects (53). In the context of refractory pain, an opioid switch may permit better analgesia with fewer opioid side effects (54).

There are emerging pediatric data on the practice of opioid rotation in children with cancer (55). Following a review of opioid prescription at the Children's Hospital at Westmead in Sydney, Australia, for the above indications, opioid rotation was employed in 9% of all opioid prescriptions, with a positive impact on side effect control and without a significant change in pain scores.

Following a prolonged period of regular dosing with one opioid, equivalent analgesia may be attained with a dose of a second opioid that is smaller than that calculated from an equianalgesic table. An opioid switch is usually accompanied by a reduction in the equianalgesic dose (approx 50% for short half-life opioids). In contrast to short half-life opioids, the doses of methadone required for equivalent analgesia after switching may be on the order of 10-20% of the equianalgesic dose of the previously used short half-life opioid. Protocols for methadone dose conversion and titration have been documented for adults (56,57).

4.5.5. Opioid Side Effects

Children do not necessarily report opioid side effects voluntarily (e.g., constipation, pruritus, dreams, etc.) and should be asked specifically about these problems. An assessment of opioid side effects is included in an assessment of analgesic effectiveness. All opioids can potentially cause the same constellation of side effects. If opioid side effects limit opioid dose escalation, then consideration should be given to an opioid switch. Tolerance to some opioid side effects (e.g., sedation, nausea and vomiting, pruritus) often develops within the first week of starting opioids. Children do not develop tolerance to constipation, and concurrent treatment with laxatives should be provided.

There is a tendency to attribute any new adverse effects to the opioid therapy. Although warranted on occasion, it should not be assumed. Other potential causes should always be considered and ruled in or ruled out by noninvasive measures, with the temporal relationship to opioid administration and an understanding of biological and elimination half-lives all part of the equation. Adverse effects may carry greater import when occurring in children than in their adult cohort. Children do far less in the way of "bargaining" with the side effects they experience. Children live in the moment, with wishes and expectations for immediate gratification. They have little to no understanding of the cause-and-effect relationship likely contributing to their lack of patience with adverse medication-related effects despite any conferred benefit (58).

Consider that a given opioid provides excellent pain relief but is making the child feel some way they dislike, such as itchy. Unlike most adults, children do not tend to understand or rationalize that sticking with it or adding another medication to reduce the pruritus will be beneficial. This tends to result in more frequent opioid rotation in children compared with adults, an observation noted in clinical experiences. To ensure ongoing trust and the child's overall comfort, any potential side effects must be anticipated and proactively managed.

Confusion can be one of the more distressing adverse effects, sometimes much more so for those close to the child than for the child as the child is sometimes unaware or distanced from awareness of his or her confusion. To lose aspects of the child's personality through medications rather than, or in addition to, illness or death is profoundly tragic. It can also frequently be prevented or ameliorated through judicious analgesic titration, opioid rotation, and the use of adjuvant therapies to widen the "therapeutic window" and minimize drug-related toxicities while ensuring pain relief.

When the confusion is attributed to opioid toxicity, whether it is idiosyncratic or dose related, the move to an alternate opioid is an appropriate one in the setting of confusion. Even if the child is unaware of his or her confusion, this kind of drastic change in the child's personality is profoundly distressing to those in attendance, the family, friends, and health professionals. However, the decision to make a change in the analgesic therapy should be based on several factors, including the expected proximity to the child's death, what the anticipated time course would be for effective pain relief with the analgesic alternative, and the attendant side effect profile. If those factors are not favorable, it may be preferable to initiate and maintain sedation until death, without agitation or other apparent distress (59).

4.5.6. NMDA Receptor Antagonists

NMDA receptor antagonists depress central sensitization in animal experiments and in humans (60-63). Dextromethorphan, dextrorphan, ketamine, memantine, and amantadine, among others, have been shown to have NMDA receptor antagonist activities. The clinical usefulness of some of these medications is compromised by a high ratio of adverse side effects to analgesia. There are no data of their utility in pediatrics other than for procedural pain management. Despite this, clinical usage is increasing, particularly in the setting of severe neuropathic pain and rapid opioid dose escalation and perceived tolerance.

4.5.7. Invasive Approaches to Intractable Pediatric Cancer Pain Anesthetic Approaches

The experience of using regional anesthesia for children with intractable pain is limited. A retrospective study of children with terminal cancer (28) showed that regional anesthesia may be appropriate in a highly select subset of children. The indications for regional anesthesia in this group were mostly related to either dose-limiting side effects of opioids or relative opioid unresponsiveness in patients for whom pain was confined to one region of the body. Rapid intravenous opioid dose reduction was required in some cases (28). Neurosurgical Approaches

Experience with neurodestructive procedures in children is also limited, as described by the experience of cordotomy in children (64) with intractable pain. It is unclear whether these cases may now have been effectively managed by current pharmacological techniques. Other Physical Approaches

Although prominent in clinical practice, there is little in the published literature about such modalities as radiotherapy, radiopharmaceuticals, and transcutaneous nerve stimulation, generally used concurrently with other pain management techniques. A case series reported some benefit for 29 children with symptomatic metastatic neuroblastoma sites treated with palliative radiotherapy (65). Similarly, the use of strontium-89 was reported for pain relief in children treated for metastatic disease, but the numbers were too small to be able to make any suggestions for clinical care (66). Sedation as a Therapeutic Modality for Refractory Pain

The use of sedation in the setting of refractory pain generally assumes that therapies beyond the conventional have been utilized, and that there is no acceptable means of providing analgesia without compromising consciousness. This trade-off between sedation and inadequate pain relief requires the consideration of the wishes of the child (as appropriate) and the child's family. The ethical issues surrounding prolonged sedation in pediatrics, including the principle of double effect, have been previously discussed (59,67,68). The continuation of high-dose opioid infusions in these circumstances is recommended to avoid situations in which a patient may have unrelieved pain but inadequate clarity to express pain perception. A variety of drugs have been used in this setting, including barbiturates, benzodiazepines, and phenothiazines (59,67-70).

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