Supportive Oncology


If pain is not adequately reduced, in the absence of treatment-limiting side-effects an increase in the ATC opioid dose may be considered in an effort to reduce the frequency or intensity of breakthrough pain. Examples of potent opioid agonists used for managing background pain include:


• transdermal fentanyl; • controlled-release oxycodone; • extended-release hydromorphone; •


• extended-release oxymorphone.


These drugs are characterized by a slow onset of action and their pharmacokinetic profiles have minimal peaks and troughs that result in stable blood levels over the dose period.7


Studies have shown that


increasing the ATC opioid medication may result in improved background and breakthrough pain.8,9


Even though these studies are on


a small scale, optimization of ATC opioid dose is a potential strategy for managing breakthrough pain, with the opioid dose being lowered again if the patient experiences adverse effects between episodes of breakthrough pain.10


Adjuvant Analgesics


In addition to these steps, the use of adjuvant drugs can be considered at all stages of the patient’s illness and at each step of the WHO analgesic ladder.11


Adjuvant analgesics are a diverse group of drugs that were originally developed for a primary indication other than pain. Many of these medications are currently used to enhance analgesia under specific circumstances. Of interest, a few of these agents are currently used as primary analgesics for specific pain conditions as well as adjuvants in some other pain conditions.12


Adjuvant analgesics (e.g.


antidepressants, anticonvulsants, N-methyl-D-aspartic acid antagonists, corticosteroids, and topicals) can be administered alone, but they are usually accompanied by acetaminophen/NSAIDS and opioids.11


Adjuvant


analgesics are widely used, especially for the relief of neuropathic cancer pain, which can present with a component of breakthrough pain.13,14


Supplemental Analgesia


The use of supplemental doses of analgesics is the cornerstone of pharmacologic treatment strategies for managing breakthrough pain. This type of medication is taken as required, rather than on a regular basis. The ideal supplementary analgesic should be efficacious, with a rapid onset, relatively short duration of action, and minimal adverse effects. It can be used either prophylactically, for predictable volitional incident pains or procedural pains, or at the onset of breakthrough pain for unpredictable spontaneous pain or non-volitional incident pains.2


For this reason, in the majority of cases the most appropriate supplemental medication will be an opioid analgesic.


The most common method of providing supplemental medication is with oral short-acting formulations of morphine and other opioid analgesics.


18


Non-opioid analgesics and adjuvant analgesics have been used/ investigated as supplemental medication for episodes of breakthrough pain, but they typically have a slow onset and relatively long duration of action.15–17


Fentanyl citrate, a synthetic opioid, has a rapid onset of effect and a short duration of action,23


matching the temporal characteristics of


a breakthrough pain episode. Furthermore, its high lipophilicity makes a number of routes of administration feasible, including oral transmucosal. The US and European approval of oral transmucosal fentanyl citrate (OTFC), a lozenge impregnated with fentanyl designed to dissolve slowly in the mouth, was an important advance in breakthrough pain treatment. It provides a non-invasive method of administration and has demonstrated a faster onset of relief and greater degree of breakthrough pain relief than oral morphine.24,25


In addition, a Cochrane


review confirmed the effectiveness of this modality for treating breakthrough pain and reported that OTFC produced faster/greater analgesia than oral morphine.22


A second oral transmucosal product with marketing authorization in the US and Europe is the effervescent buccal fentanyl tablet.26


This tablet


provides rapid penetration of fentanyl through the buccal mucosa by using effervescence to cause pH shifts that enhance the rate and extent of fentanyl absorption. The efficacy of this formulation has been shown in placebo-controlled studies that demonstrated an analgesia onset that was faster than would be expected from oral therapy.27–30


Mucoadhesive film formulations of fentanyl for buccal or sublingual absorption aimed at rapid relief from breakthrough pain are also


US ONCOLOGY & HEMATOLOGY


Despite their short-acting nature, the pharmacokinetic/pharmacodynamic profiles of these oral opioids (onset of action: 30–40 minutes; duration of effect: about four hours) do not tend to mirror the temporal characteristics of most breakthrough pain episodes.4


For this reason, these oral opioid


formulations are most effective for predictable incident breakthrough pain, for which they can be given 30–45 minutes before a known triggering activity. Efforts to deliver rescue medication more effectively have explored alternatives to the oral route, including parenteral, rectal, inhaled, intranasal, sublingual, and oral transmucosal preparations.


methadone, morphine (controlled-, sustained- and extended-release formulations); and


Parenteral Opioids


The parenteral routes of opioid administration (intravenous and subcutaneous) have been shown to be effective, well tolerated, and safe for the management of breakthrough pain.18,19


The use of parenteral opioids is, however, associated with several disadvantages. For example, any indwelling intravenous catheter can become a site of infection and thus requires skilled nursing attention if the patient is unable to care for catheter access.20


more costs are involved as this route requires preparation of the opioid solution for injection by the pharmacist and administration of the infusion via an external pump.20


Despite this, the rapid onset of action


associated with this route of administration means that it may be acceptable in cases where the breakthrough pain is severe.21


Oral Transmucosal Opioids


The mouth provides a large mucosal surface for drug absorption, allowing drugs to enter the systemic circulation directly, bypassing the gastrointestinal tract and first-pass metabolism in the liver.


The oral transmucosal routes of administration (buccal and sublingual) have increasingly been used in the management of breakthrough pain episodes.22


In addition to this,


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