Consensus Panel Recommendations: Routes of Administration

28 Apr

Routes of AdministrationBecause the time from onset to peak pain intensity of BTP is generally only a few minutes and the average duration is one-half hour, the opioid that is used to manage most cases of BTP should have a rapid onset of effective analgesia and a duration of action appropriate for the characteristics of the BTP.

Oral and Oral Transmucosal Routes

Morphine, hydromorphone, and oxycodone are the oral opioids most often used to treat BTP when they are administered in their IR formulations of tablets, capsules, or liquid concentrates (Table 1). However, these agents typically have an extensive first-pass effect and are hydrophilic in nature, which slows the onset of analgesia to approximately 30 minutes or more. In the opinion of the Consensus Panel, this makes these three opioids less well suited for severe idio pathic or unpredictable incident BTP. Oral IR opioids, however, may be appropriate in patients with predictable incident pain when they are given 30 to 45 minutes before the precipitating event (such as movement).

Table 1   Characteristics of Immediate-Release Opioids Useful for Breakthrough Pain (BTP)


Immediate-Release opioidOnset of Analgesia


of Effect

Advantages (A)/Disadvantages (D)
Morphine (oral)

30-40 minutes

4 hours

A — available in multiple dosage forms, liquid concentrate D — slow onset of analgesia for idiopathic BTP
Oxycodone (oral)

30 minutes

4 hours

Same as morphine
Hydromorphone (oral)

30 minutes

4 hours

D — no liquid concentrate, slow onset of analgesia for idiopathic BTP
Methadone (oral)

—10—15 minutes

4-6 hours

A — faster onset of analgesia in one small study D — complex pharmacology, pharmacokinetics


Fetanyl (transmucosal)

~5-10 minutes

1-2 hours

A — fastest onset of analgesiaD — requires ongoing patient cooperation in use

Although methadone is commonly used in other settings because of its longer duration of action, recent evidence suggests that it may have a role in the management of BTP as a result of its relatively rapid onset of action. Caution is essential with frequent dosing of methadone because of its long elimination half-life and the potential for accumulation, resulting in toxicity.

Fentanyl, by contrast, is well suited for absorption through the oral mucosa with minimal local irritation. These attributes led to the development of and the FDA’s subsequent approval of oral transmucosal fentanyl for BTP. The oral transmucosal delivery system incorporates fentanyl citrate within a matrix of sucrose fitted onto a plastic handle for dissolution within the oral cavity.

For all opioids, ongoing reassessment and titration are critical for successful pain relief and for minimizing the risk of clinically significant adverse events. Only clinicians with experience in the use of opioids should prescribe them.
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Parenteral Route

The parenteral administration of opioids may serve as an important alternative to the oral route, mainly in patients experiencing multiple daily episodes of BTP that respond poorly to oral opioids. However, even though parenteral opi-oids are used extensively in inpatient and hospice settings, technical problems limit their use in the outpatient setting to carefully selected patients, including those with pain refractory to more standard approaches.

Rectal Route

Administration of medication through the rectum is an alternative route, although the onset and peak effects lag behind those necessary for managing BTP. There is also considerable variability in the medication’s absorption among patients and within the same patient. Only morphine and hydromorphone are commercially available as a rectal suppository.

Sublingual and Intranasal Routes

Because of its highly vascular nature, the oral cavity is also used as a site for local rapid absorption of opioids. Sublingual morphine has been used for many years in patients with terminal cancer, but this route of administration is less than ideal as a result of its bitter taste and its delayed onset of action, caused by poor absorption.

Preliminary evidence suggests that sublingual sufentanil solution, sublingual buprenorphine (Subutex®, Reckitt Benckiser), and fentanyl and alfentanil sprays provide rapid, effective pain relief. Various opioids have also been administered via the intranasal route, including morphine, sufentanil, and fentanyl. These unique delivery systems await further investigation for use in daily clinical practice. buy tadacip


The best method of determining the most effective dose of an opioid for BTP remains unclear. Guidelines have advocated a fixed proportion of the daily maintenance dose, typically in the range of 5% to 17% of the total daily dose. However, BTP may vary in cause, severity, and duration, and the dose of medication for BTP may need to be titrated in much the same way as the dose of opioid is titrated for baseline persistent pain.

Little correlation exists between the daily opioid dose and the dose needed for BTP. Given this disparity, the dose of an IR opioid should be tailored to the individual according to:

  • the onset of the BTP episode.
  • the duration of BTP
  • the patient’s tolerance to the IR opioid used.

Patients who are already taking opioid therapy may require a higher initial opioid dose than opioid-naive patients.

Case Study (continued)

A reassessment and review of T. G.’s pain diary reveals several predictable episodes of BTP. Most episodes of BTP are linked to activity, especially when she stands or walks. The characteristic of the BTP is similar to her baseline persistent pain.

T. G. wishes to restore her ability to work around her home as much as possible until the pain-relieving effects of the radiation therapy occur. A trial of immediate-release (IR) morphine 30 mg orally 30 minutes prior to any of these predictable episodes of BTP is initiated with the understanding that this dosage will be re-evaluated in one week. silagra tablets

T. G. is reminded to document her episodes of BTP, including her response to her pre-emptive dose of morphine. She is also reassured that if this dose proves ineffective in reducing the overall severity of BTP, it will be titrated to effect, just as her sustained-release morphine was adjusted for her baseline persistent pain.

The patient’s response to therapy should be reassessed on a frequent basis, especially after changes in the management regimen have been made. If more than four episodes of BTP occur within a 24-hour period, an increase in the total daily dose of opioid for the baseline persistent pain should be considered.

This situation would be viewed as different from one in which a patient has predictable incident BTP and is using a scheduled dose of an IR opioid.