An Assessment of the Safety, Eff icacy, and Acceptability of Intranasal Fentanyl Citrate in the Management of Cancer-Related Breakthrough Pain

Vol. 20 No. 4 October 2000

Journal of Pain and Symptom Management

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Original Article

An Assessment of the Safety, Efficacy, and Acceptability of Intranasal Fentanyl Citrate in the Management of Cancer-Related Breakthrough Pain: A Pilot Study Giovambattista Zeppetella, BSc (Hons), MRCGP St. Joseph’s Hospice, and Royal Hospitals NHS Trust, London, United Kingdom

Abstract The effects of intranasal fentanyl citrate (INFC) were assessed in 12 hospice inpatients with cancer-related breakthrough pain. Patients received 20 ␮g of fentanyl citrate and were asked to rate their pain using a visual analogue scale (VAS) before INFC, then after 3, 5, 10, 15, 30, 45, and 60 minutes. Eight patients (66%) had reductions in pain scores, four within 5 minutes and seven within 10 minutes of taking INFC. Ratings for INFC were very good (5 ⫽ 42%), good (3 ⫽ 25%), moderate (1 ⫽ 8%), and bad (3 ⫽ 25%). In comparison to oral morphine, INFC was better (6 ⫽ 50%), the same (3 ⫽ 25%), or worse (3 ⫽ 25%). Nine patients (75%) said they would continue to use INFC. Of the three patients who did not experience a positive result, two were taking relatively higher baseline opioid doses and one was found to have a fracture. No systemic adverse events were noted; two patients reported nasal itching or discomfort on first use that disappeared with repeated use. Intranasal fentanyl citrate appears safe and well tolerated by these patients. Randomized placebo-controlled and dose-ranging studies are required to confirm these findings. J Pain Symptom Manage 2000: 20:253–258. © U.S. Cancer Pain Relief Committee, 2000. Key Words Fentanyl citrate, inhaled drugs, cancer, breakthrough pain

Introduction Breakthrough pain is often difficult to manage; it may be due to any one of several causes and can last only minutes. It has been suggested that analgesics and delivery systems that allow noninvasive administration, rapid absorption for quick onset, individual and episodic titration, and a short to moderate dura-

Address reprint requests to: Giovambattista Zeppetella, BSc (Hons), MRCGP, St. Joseph’s Hospice, Mare Street, London E8 4SA, United Kingdom. Accepted for publication: November 9, 1999. © U.S. Cancer Pain Relief Committee, 2000 Published by Elsevier, New York, New York

tion would greatly improve the management of this problem.1 Analgesics delivered through the intranasal route could well provide these types of advantages. A number of drugs have been administered intranasally, including midazolam,2 ketamine,3 nitroglycerin,4 and fentanyl.5 Fentanyl is a ␮-opioid receptor agonist with an analgesic potency 50 to 100 times that of morphine.6 It has been shown that lipophilic opioids, such as fentanyl, are well absorbed from the mucosal surface. The venous outflow of the nasal mucosa enters the systemic circulation bypassing the liver and avoiding the hepatic first pass effect. The bioavailability of in0885-3924/00/$–see front matter PII S0885-3924(00)00180-9

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tranasally-administered fentanyl citrate (INFC) is approximately 70%.7 INFC has been shown to be an effective analgesic in postoperative patients.5,8–10 Pain has been shown to decrease within 5 minutes and analgesia lasts for approximately an hour. The potential advantages of INFC, therefore, are that it is noninvasive and has a fast onset of action, features that are well suited to the management of breakthrough pain. To assess these features, the present study was undertaken to assess the safety, efficacy, and acceptability of INFC in the management of cancer-related breakthrough pain in terminally ill patients.

Methods Hospice inpatients complaining of breakthrough pain were entered into the study. After giving informed written consent, a record was made of their chronic pain, breakthrough pain (adapting the schedule used by Portenoy and Hagen11), analgesic use, and analgesic effectiveness. Patients were asked to identify the main breakthrough pain(s) for which they were requiring analgesia. For the purpose of the study, patients experiencing one type of cancer-related breakthrough pain (with characteristics suggestive of nociceptive pain) were chosen. Fentanyl citrate was administered using 10mL nasal spray bottles with a 0.2-mL reservoir; each patient received 20 ␮g of fentanyl citrate. The nasal spray bottles were designed and supplied by Go Medical Industries Pty Ltd. and deliver a 0.2-mL bolus dose with each spray. Permission was obtained from Department of Health Medicines Control Agency before commencing the trial. The bottles were prepared by the Pharmacy Department at the Royal London Hospitals NHS Trust. Fentanyl citrate injection (10 mL) was drawn up in a 10-mL syringe and filtered through a 5-␮m filter into each bottle. The bottles were then capped with the spray assembly and tested to ensure that the spray was functional. Nonfunctional spray bottles were rejected. A tamper-evident seal was applied to each passed bottle. Patients were first shown how to use the nasal spray bottles. Before commencing the trial, patients tried a practice spray. If pain was completely relieved patients were to continue with one spray, if partial or no relief resulted, pa-

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tients were given a second bottle so that each nostril could be sprayed. All patients required two bottles (i.e., 0.4 mL of 50 ␮g/mL fentanyl citrate, equivalent to 20 ␮g fentanyl citrate). Patients were asked to use INFC for five consecutive episodes of breakthrough pain. Pain was assessed using a visual analogue scale (VAS) before INFC and at 3, 5, 10, 15, 30, 45, and 60 minutes after. Changes in either primary or secondary analgesics were not permitted during the trial. Analgesics taken before the trial were continued with no change in dose; short-acting oral morphine was available as rescue medication. Patients were monitored during the study period for adverse events and at the end of the study period were asked: • whether they had experienced any adverse events; • how they rated this method of taking medication to control pain; and • to list the advantages and disadvantages of this method of taking medication to control pain. Ethical committee consent to the trial was obtained from the Hospice.

Results Twelve patients were recruited into the study (average age 73 years). Details of their diagnosis and the cause and characteristics of their breakthrough pains are shown in Table 1. In nine patients (75%), the site of breakthrough pain was related to the primary cancer; in the remainder, secondary cancer was the cause. The average number of daily pain episodes was five, with 50% of patients rating the severity as severe or excruciating. Patients often gave a range for the duration of the breakthrough pain episode; in eight patients (66.6%), the pain lasted 30 minutes or less. All patients took short-acting morphine for breakthrough pain. On average, rescue medication was used twice daily (range 1–5). Pain relief from rescue medication was rated as good (four patients ⫽ 33%), fair (five patients ⫽ 42%), and poor (three patients ⫽ 25%). Following INFC eight patients (66%) had reductions in their VAS scores. Four of them had pain reduction at 5 minutes; this increased to seven at 10 minutes. The same eight patients gave their verbal rating of INFC as an analgesic

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Table 1 Characteristics of Breakthrough Pain in Patients Surveyed Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 aMild.

Sex

Age (years)

Primary cancer

Main site of pain

M M M M M M F F M F M M

82 61 65 71 58 71 77 78 83 74 86 69

Bladder Lung Pancreas Unknown Lung Lung Bladder Cervix Stomach Stomach Lung Esophagus

Suprapubic Hip Back Spine Chest Chest Suprapubic Suprapubic Epigastric Epigastric Chest Right hypochondrium

Severitya

Daily frequency

Onset

Duration (min)

Precipitant

Predictable

Moderate Excruciating Moderate Severe Severe Moderate Moderate Severe Severe Moderate Moderate Severe

4 8 7 9 2 6 4 5 2 3 6 4

Gradual Sudden Gradual Sudden Sudden Gradual Sudden Sudden Gradual Sudden Gradual Gradual

60 60–90 60–90 15–20 20–30 30–60 30–40 15–30 30–40 30 20–30 45–60

None Incident None Incident Incident None None Incident None None None None

No Yes No Yes Yes Yes No Yes No No Yes No

moderate, severe, excruciating.

as good or very good (Table 2). The mean percentage change in VAS scores for the 40 breakthrough pain episodes in these eight patients is shown in Figure 1. Nine patients (75%) rated INFC as effective or better than morphine; this included patient no. 2, whose VAS scores had not shown significant falls. Four patients (33%) rated INFC as moderate or bad; the mean percentage change in VAS

scores for the 20 episodes of breakthrough pain in these patients is shown in Figure 2. There appeared to be a relationship between the dose of regular analgesia and the change in VAS scores. Patients on the lowest doses of daily morphine showed a fall in their VAS scores, whereas those on a daily morphine equivalent of 120 mg or more did not. Two patients required their usual rescue

Table 2 Patient Rating of Intranasal Fentanyl Citrate Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 aVery

Regular analgesia CR morphine 90 mg bd Fentanyl TTS 25 ␮g/hr CR morphine 60 mg bd Morphine 5 mg 4 hourly CR morphine 20 mg bd CR morphine 30 mg bd Morphine 5 mg 4 hourly CR morphine 30 mg bd CR morphine 30 mg bd Morphine 5 mg 4 hourly Morphine 2.5 mg 4 hourly Morphine 30 mg 4 hourly

INFC rating as an analgesic for BTPa

Rating compared to morphineb

Advantages

Bad

Worse

None

Unhelpful

No

Moderate

The same

Quicker

None

Yes

Bad

Worse

None

No

Very good

Better

Yes

Very good

Better

Convenient, no taste Easy to take

Nasal itching, sneezing None None

Yes

Good

The same

None

Yes

Very good

Better

Yes

Good

Better

Uncomfortable at first None

Good

The same

None

Yes

Very good

Better

None

Yes

Very good

Better

None

Yes

Bad

Worse

Not as good as morphine

No

Quick and easy to use Took pain away more quickly Gave me more control None No sleepiness or sickness Worked more quickly than morphine No bitter taste of morphine

good, good, moderate, bad, very bad. better, the same. INFC ⫽ intranasal fentanyl citrate, BTP ⫽ breakthrough pain, CR ⫽ controlled-release.

bWorse,

Disadvantages

Would you continue with this treatment?

Yes

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Fig. 1. Mean percentage change in visual analogue scale scores for patients reporting benefit from INFC.

medication during the study despite taking INFC. Patient no. 1 took two doses of short-acting morphine at 15 and 30 minutes after taking INFC; patient no. 12 took three doses, once at 20 minutes and twice at 30 minutes. All patients were monitored for local and systemic adverse events. Two patients described nasal discomfort and nasal itching when first

using INFC (Table 2), which disappeared with repeated use. No systemic adverse events were reported by patients or observed by staff. A number of advantages were volunteered by patients, including convenience, ease of use, and fast onset of action. No disadvantages were described with respect to the mode of administration. Nine patients (75%) said they would have

Fig. 2. Mean percentage change in visual analogue scale scores for patients reporting no benefit from INFC.

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Intranasal Fentanyl for Breakthrough Pain

continued the treatment if it were available. The remaining patients were dissatisfied with the efficacy rather that the delivery system.

Discussion Breakthrough pain is a common clinical problem; management is complicated by its heterogeneity. In this survey, breakthrough pain occurred frequently, was often severe or excruciating, and was usually short lasting. Fentanyl is a potent, lipophilic, short-lasting analgesic. These characteristics, together with the noninvasive nature of an intranasal spray, make INFC potentially ideal in the management of breakthrough pain. For the purpose of this study, patients with nociceptive breakthrough pain were chosen since this type of pain is usually responsive to opioids, although there is evidence to suggest fentanyl could also be helpful in neuropathic pain.12,13 Current guidelines for the use of morphine recommend that the dose of rescue medication should be the four hourly equivalent dose.14,15 The oral morphine equivalent of 20 ␮g INFC is approximately 2–4 mg, assuming a 70% bioavailability of INFC,7 a fentanyl potency 50 to 100 times morphine,6 and an oralto-intravenous morphine ratio of 1:3.16 Three patients taking more than the four hourly morphine equivalent of 20 mg (patients no. 1, 3, and 12) failed to respond to INFC. Patient no. 2, prescribed transdermal fentanyl, had particularly severe pain, which was subsequently shown to result from a pathological fracture. This patient later required much higher background analgesia and surgical intervention. Approximately half of the remainder responded to INFC despite the relatively small dose. The relationship between INFC as rescue medication and the total daily dose of scheduled opioid may not be straightforward; similar findings have been found for oral transmucosal fentanyl citrate (OTFC).17 This would suggest that patients should be started on a relatively low initial dose that is subsequently titrated to the optimal dose (as in the case with OTFC) and that patients no. 1, 3, and 12 may have responded by increasing the dose of INFC. All patients surveyed took oral morphine as rescue medication. Short-acting oral morphine takes approximately 1 hour to reach its maxi-

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mum concentration and analgesia lasts for about 4 hours.18 Breakthrough pain can occur several times a day and may last for short periods; eight of the patients’ breakthrough pains lasted for 30 minutes or less. The effects of short-acting morphine may thus continue well beyond the duration of the pain and repeated dosing can lead to adverse events. INFC is delivered as a bolus dose directly to its site of absorption and appears to work within 10 minutes of administration. The rapid onset and short duration of action could make this preparation more appropriate than short-acting morphine for breakthrough pain. Although INFC’s high initial peaks could cause adverse events, this was not seen in this survey. When rapid pain relief is required, parenteral opioids are usually given. These can be invasive, inconvenient, and uncomfortable. The nasal mucosa allows rapid and painless absorption of fentanyl. Absorption appears to depend on the lack of effect on mucociliary function.19 Fentanyl at a concentration of 50 ␮g/mL has been shown to have a low toxic effect on human nasal epithelial tissue20 and is therefore safe in chronic nasal administration. For patients unable to tolerate morphine (patient no. 2), INFC could provide a logical alternative to be given alongside the long-acting transdermal fentanyl preparation. Most patients tolerated the intranasal spray well, including those who felt it was an inadequate analgesic. Furthermore, INFC, unlike parenteral opioids, is easy to administer by patients and/or caregivers alike. In addition to an effect in nociceptive pain, INFC may have a role in neuropathic pain12,13 and where treatment procedures, such as physiotherapy and dressing changes, can be painful. A further important application is in the patient’s home where the caregiver could administer INFC for breakthrough pain to a patient unable to take oral medication without calling in a health care professional. To provide the flexibility required for treating breakthrough pain, a range of INFC doses would be necessary. The volume of INFC is limited to 0.2 mL. With larger volumes, most of the drug is likely to be swallowed. More concentrated preparations could be prepared from crystalline fentanyl citrate, although the effects on human nasal epithelial tissue would have to be investigated. An alternative would

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be to use sufentanil, a potent short-acting opioid 10 times more potent than fentanyl. Like fentanyl, it has been used successfully by the intranasal route21,22 and has little effect on mucociliary function.20 Most patients surveyed found INFC helpful. It provided rapid pain relief in a simple, controllable, safe, and patient-friendly manner. Neither patients nor staff reported any adverse events at the trial dose. Randomized placebocontrolled and dose-ranging studies are now required to determine the role of INFC in the management of cancer-related breakthrough pain.

Acknowledgments This work was funded by the Janssen Research Foundation; in particular I would like to thank Mark Travers and Liz Wager for their advice and support. I would also like to thank Go Medical Industries Pty Ltd. for supplying the nasal spray bottles and the Pharmacy department at the Royal Hospitals NHS Trust for filling them.

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