Fentanyl is an opioid analgesic drug. The transdermal delivery system is intended to allow the passive diffusion of the medication over a long period of time while maintaining a constant therapeutic dose. Transdermal fentanyl has been evaluated for the management of chronic cancer-related pain. Transdermal fentanyl also has been examined in relation to opioids by other routes for its effect on opioid-related constipation. The use of transdermal fentanyl in patients who are not opioid tolerant and for acute pain is contraindicated due to a risk of life-threatening hypoventilation.
Recommended for Practice
Research Evidence Summaries
Chang, J.T., Lin, C.Y., Lin, J.C., Lee, M.S., Chen, Y.J., & Wang, H.M. (2010). Transdermal fentanyl for pain caused by radiotherapy in head and neck cancer patients treated in an outpatient setting: A multicenter trial in Taiwan. Japanese Journal of Clinical Oncology, 40(4), 307–312.doi: 10.1093/jjco/hyp166
To evaluate the effectiveness of transdermal fentanyl (TF) for pain management in patients with head and neck cancer receiving radiotherapy; to evaluate the effectiveness, safety, and long-term tolerability of TF after initial administration
Intervention Characteristics/Basic Study Process:
Patients entered in the trial were instructed in the use of TF. Initial TF dose was 25 mcg/hour, and patches were replaced every three days. Dose was titrated upward as needed, in 25 mcg/hour increments. Patients requiring more than 50 mcg/hour were allowed to use multiple patches to achieve the required dose. Doses greater than 100 mcg/hour were used in exceptional circumstances only. As a treatment for breakthrough pain, patients received immediate-release morphine to be administered as needed, every 2–4 hours. Use of all rescue medications was recorded. Pain was measured by means of a questionnaire that was administered at study entry and after 7, 14, 28, 35, and 42 days. Amount of rescue analgesics and data about constipation, diarrhea, and use of laxatives and antidiarrheals were recorded by patients daily. Investigators summarized the data at each study visit.
- Initially, the sample was composed of 163 patients. The size of the sample at the end of the study was 108 patients.
- Mean patient age of the final sample was 53 years. Age range was 24–68 years.
- Of all patients, 9.2% were female and 90.8% were male.
- All patients had head and neck cancer and were receiving radiation therapy. Most were taking nonsteroidal anti-inflammatory drugs, codeine, and tramadol. Of all patients, 11% were taking morphine at the time of study entry, and 57.7% were receiving chemotherapy. The average radiation dose over 42 days was slightly under 7000 cGy. Initial pain scores for 44.2% of patients were equal to or greater than 7.
- Visual analog scale (VAS), to measure pain
- Wisconsin Brief Pain Inventory (BPI), short version, to measure pain
- Five-point Likert scale (0 = fully awake, 4 = drowsy most of the time), to measure daytime drowsiness
- Five-point Likert scale (0 = no symptoms), 4 = very severe), to measure nausea or vomiting
- National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3, to measure adverse effects
- The most commonly used dose of TF was 25 mcg/hour at days 0, 7, 14, 21, and 28.
- Of patients treated by radiotherapy alone, 7% received a dose of TF that was larger than 25 mcg/hour. Of patients who also received chemotherapy, 34.8% required a dose larger than 25 mcg/hour.
- VAS pain scores declined in all patients, but authors reported no statistical significance. By day 42, VAS scores indicated no further decline in pain.
- Scores in each domain of the BPI improved after one week and on days 7 (p < 0.05) and 28 (p < 0.0001). BPI scores improved significantly.
- Of patients in the initial sample, 55 patients (34.4%) had dropped out by the second week of treatment. They dropped out because of side effects. Twenty additional patients (12.3%) did not complete the study because of interruption of radiotherapy due to sepsis, the fact that TF was no longer needed, grade 3–4 vomiting (23.9%), nausea (16.6%), somnolence (4.9%), or dizziness (4.9%)
Data suggest that TF can be effective and relatively easy to use, in an outpatient setting, for patients receiving radiotherapy; however, TF was accompanied by a high rate of severe side effects.
- The study had a risk of bias due to no appropriate control group.
- The study had a very high dropout rate due to side effects.
- Authors provide no statistical analysis over time of VAS score changes or other score changes.
- The reported findings related to side effects were confusing. Authors stated that, initially, 55 patients dropped out due to side effects and that another 20 patients did not complete the study. The actual prevalence and severity of side effects is unclear.
Additional research regarding various approaches to pain management, in the cited population, is needed.
Kress, H.G., Von der Laage, D., Hoerauf, K.H., Nolte, T., Heiskanen, T., Petersen, R., . . . Jensen, N.H. (2008). A randomized, open, parallel group, multicenter trial to investigate analgesic efficacy and safety of a new transdermal fentanyl patch compared to standard opioid treatment in cancer pain. Journal of Pain and Symptom Management, 36(3), 268–279.doi: 10.1016/j.jpainsymman.2007.10.023
To compare, in clinical practice, the effect and safety of a new matrix fentanyl patch (Fentanyl Improved Transdermal [FIT]) patch) to oral and other transdermal opioid treatment
Intervention Characteristics/Basic Study Process:
Patients were randomly assigned to either FIT patch or standard opioid treatment via oral or transdermal route. Morphine was the only rescue medication allowed. Patients could receive radiotherapy and chemotherapy as well as nonpharmacologic and pharmacologic pain management therapies. Patients randomized to FIT therapy switched from existing regimens to FIT therapy by means of standard conversion ratios. Patients had an initial screening visit and four additional visits. Each evening each patient assessed his or her pain and recorded the pain rating in a diary. Adverse events were monitored in follow-up visits through the 30-day trial period and for one week longer. Patients assessed adverse events on a four-point scale and recorded the rating.
- The sample of patients who completed the trial was composed of 170 patients.
- In the FIT group, mean patient age was 63.1 years (SD = 11.04 years). In the control arm, mean patient age was 61.3 years (SD = 11.66 years).
- Of all patients, 40% were female and 60% were male.
- Overall, 11% of patients randomized were opioid naive.
- Authors did not report cancer diagnoses. All patients had a baseline Karnofsky performance score of 50 or higher.
- Seven European countries
Randomized open-label parallel-group design
- Numeric rating scale (0–10), to measure pain intensity
- Four-point scale to rate adverse events, including constipation, nausea, sleep disturbance, and daytime drowsiness
- There was no significant difference between groups regarding pain intensity ratings.
- Subgroup analysis revealed no differences based on concomitant chemotherapy or radiotherapy or on subgroup analysis based on nocioceptive versus neuropathic pain.
- Between groups, there were no significant differences in the prevalence or severity of adverse effects.
- Authors observed no new or unexpected adverse drug reactions.
Results showed no differences, in terms of pain management or adverse effects, between the new transdermal patch and standard transdermal or oral opioid treatment. Findings suggest that the new type of patch is safe and, in terms of efficacy, similar to standard treatments.
- The study has a risk of bias due to no appropriate control group.
- Authors provided no analysis of other medications or approaches used for pain management. (These were not controlled in the study.) Authors did not report analysis of morphine use for breakthrough pain.
- Patients' diaries were the source of adverse events and pain intensity scores. Note, however, that authors stated that patients' records regarding rescue medication, for example, could not have been accurate. If patients' records were inaccurate, the study should have provided objective or observer scoring.
Transdermal fentanyl, delivered by means of conventional patch or FIT patch, is an effective means of controlling cancer pain.
Marinangeli, F., Ciccozzi, A., Aloisio, L., Colangeli, A., Paladini, A., Bajocco, C., . . . Varrassi. G. (2007). Improved cancer pain treatment using combined fentanyl-TTS and tramadol. Pain Practice, 4, 307–312.doi: 10.1111/j.1533-2500.2007.00155.x
To facilitate dose escalation of strong opioids by using an opioid-tramadol combination
Intervention Characteristics/Basic Study Process:
Of 70 patients, 35 were treated conventionally, with increasing transdermal fentanyl (group F). The other 35 patients received oral tramadol added to their fentanyl before each increment of their transdermal opioid (group T). Patients started fentanyl therapy by taking 25, 50, 75, or 100 mcg/hour, the amount based on equianalgesic dosing. Maximum tramadol dose was 400 mg/day. Rectal tramadol was not used.
- The sample was composed of 70 patients with intractable cancer pain whose visual analog pain score was greater than 3.
- All patients were receiving palliative care and not in the active treatment phase of disease.
The study was conducted in Italy.
Randomized open-label, prospectively evaluated study
Authors used a visual analog scale (VAS) to measure pain.
- In group F, 33 patients completed the study; in group T, 34 patients completed the study.
- Pain was equal in both groups; VAS scores did not differ. However, pain control in the tramadol group was achieved at slower escalation of fentanyl dose. The combination of a strong opioid with a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination minimized periods of overdosing and underdosing.
- Application time for patches was significantly higher in group T. In group T, no patient's fentanyl patch dose changed before the patient reached the maximum tramadol dose of 400 mg per day.
- Regarding adequacy of treatment, patients’, relatives’, and physicians’ judgments did not differ.
The combination of a strong opioid and a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination treatment minimized periods of overdosing and underdosing. Combination treatment as specified is a useful alternative, especially when disease and pain progress quickly.
Severe nausea and vomiting occurred in six patients in group T and three in group F, possibly due to a synergistic effect between fentanyl and tramadol. This study was insufficiently powered to show statistically significant differences relating to uncommon or serious side effects.
The greater number of fentanyl dose changes associated with higher fentanyl consumption in group F may support the hypothesis that tolerance is a pharmacologic effect, rather than a result of the rapid progression of disease. Additional study of the synergistic effect of tramadol and fentanyl, with respect to severe nausea and vomiting, is needed.
Mercadante, S., Porzio, G., Ferrera, P., Fulfaro, F., Aielli, F., Verna, L., . . . Mangione, S. (2008). Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. European Journal of Pain (London, England), 12(8), 1040–1046.doi: 10.1016/j.ejpain.2008.01.013
To compare, in patients with advanced cancer, the analgesic efficacy, adverse effects, and effect on quality of life of morphine, fentanyl, and methadone
Intervention Characteristics/Basic Study Process:
Patients were randomized to morphine, fentanyl, or methadone. Morphine was offered as breakthrough pain medication at one-sixth the equianalgesic 24-hour dose. Adjuvant medications were allowed. If the patient experienced poor opioid response or uncontrolled adverse events, he or she switched to another opioid. Data were collected at four weekly intervals.
- The sample was composed of 108 patients, 36 in the morphine group (22 patients in this group completed the study), 36 in the fentanyl group (25 completed the study), and 36 in the methadone group (23 completed the study).
- In the morphine group, mean patient age was 59 years; in the fentanyl group, 57 years; and in the methadone group, 61 years.
- In the morphine group, 10 patients were female; in the fentanyl group, 14 were female; and in the methadone group, 12 were female. In the morphine group, 12 patients were male; in the fentanyl group, 11 were male; and in the methadone group, 11 were male.
- Patients had advanced cancer with pain and required first-line opioids for pain control. Patients were excluded from the study if they had liver or renal disease, cognitive impairment, or expected survival of less than three months; if they were undergoing radiation therapy or a new course of chemotherapy; or if they had prevalent incident pain, mixed pain, or nociceptive and neuropathic pain. Breast cancer was the most frequent diagnosis.
- Multiple sites in Italy
Randomized controlled trial
- Scale (0 = not at all, 3 = severe), to measure adverse events
- Number of passages per day, to measure constipation
- Scale, 0–10, to measure pain intensity (PI)
- Number of daily dose changes to stabilization
- Opioid escalation index, or OEI (OMD – OSD/OSD per day x 100, where OMD represents doses administered at four weeks after study initiation and OSD represents the opioid starting dose at study initiation)
- Spitzer Quality of Life Index
- Costs of opioid therapy
- A similar number of patients in each group switched to other opioids.
- No significant differences existed in number of days to achieve dose stabilization.
- No significant differences existed in the number of dose changes needed during titration.
- No differences existed in the PI of the three groups.
- OEI% was highest in the fentanyl group and significantly lower in the methadone group; 14 patients on methadone did not have a dose change, but 8 required a decrease in the dose and then a subsequent increase.
- Authors observed no significant intergroup difference in quality-of-life scores.
- Methadone was less expensive.
All three opioids were effective in controlling cancer pain in some patients. Adverse event profiles were similar. Methadone was less expensive than fentanyl or morphine but required clinical expertise in dosing. (The doses of some patients had to decrease and then increase.)
- The study had a small sample, with fewer than 100 patients.
- The sample was a convenience sample; it was not blinded.
Long-acting morphine, fentanyl, and methadone are effective in controlling the pain of advanced cancer. Methadone is an option for patients for whom cost is a concern. Prescribing methadone requires clinical expertise.
Miyazaki, T., Hanaoka, K., Namiki, A., Ogawa, S., Kitajima, T., Hosokawa, T., . . . Mashimo, S. (2008). Efficacy, safety and pharmacokinetic study of a novel fentanyl-containing matrix transdermal patch system in Japanese patients with cancer pain. Clinical Drug Investigation, 28(5), 313–325.doi: 10.2165/00044011-200828050-00005
To evaluate the safety, efficacy, and pharmacokinetic profile of a 12.5 mcg/hour transdermal matrix fentanyl patch used to manage the persistent pain of patients with cancer
Intervention Characteristics/Basic Study Process:
On study day 1, the patch was applied. It was replaced every 3 days for a 10-day period. All patients initially received the 12.5 mcg/hour dose. At the time of patch replacement, the dose could be increased according to pain intensity and rescue medication used. Use of opioid receptor antagonist analgesics and other opioid medication was prohibited. Patients received fast-acting morphine for breakthrough pain. Serum fentanyl levels were measured on days 4, 7, and 10. Physicians assessed global effect on day 10 or at the time of study discontinuation. Patients provided a global assessment on days 1, 4, and 7.
- The sample was composed of 85 patients.
- Of all patients, 75% were age 60 or older. The age range was 40 to older than 70.
- Of all patients, 47% were female and 53% were male.
- Diagnoses included gastrointestinal cancer (which 40% of patients had), gynecologic cancer (10.6%), and hepatobiliary cancer (5.9%). The sample contained a mix of other cancer sites. At baseline, 69.4% of patients were taking oxycodone, 29.4% were taking morphine, and 1.2% were undergoing fentanyl injections for pain control.
- Single site
Open-label prospective trial
- Five-point scale (5 = very satisfied, 1 = very dissatisfied), to measure patient's global assessment of pain
- Dichotomous scale (1 = effective, 2 = ineffective), to measure physicians' global assessment
- Eastern Cooperative Group (ECOG) performance status
In 78 patients, a total of 316 adverse events occurred. The most frequent adverse events were nausea (which 36% of patients experienced), somnolence (30.2%), vomiting (25.6%), diarrhea (19.8%), constipation (16.3%), pyrexia (12.8%), and insomnia (10.5%). Three patients experienced evere adverse events: dyspnea and respiratory failure. Authors observed 12 cases of skin irritation at the patch site. Of all patients, 96% reported that they were satisfied or very satisfied with the 12.5 mcg/hour transdermal matrix fentanyl patch. According to global assessment by physicians, the 12.5 mcg/hour transdermal matrix fentanyl patch was as effective as the other treatments in 98% of cases.
The 12.5 mcg/hour transdermal matrix fentanyl patch appears to be a reasonable means of controlling persistent cancer pain in patients switching from low-dose morphine or oxycodone.
- The study had a small sample, with fewer than 100 participants.
- The study had a risk of bias due to no control or comparison group.
- Authors provided no specific severity rating of adverse effects.
- Distribution of final fentanyl doses associated with efficacy was not provided.
- Authors did not report how adverse events were defined or recorded.
- Authors did not report the use rescue medications.
- Authors stated the results of a visual analog scale over time; however, they did not describe the scale or how it was used.
No firm conclusions can be drawn from this study.
Pergolizzi, S., Iati, G., Santacaterina, A., Palazzolo, C., Di Pietro, A., Garufi, G., & Ferrau, F. (2006). Treatment planning in patients with bone metastases. Final results of a prospective study using pre-medication with fentanyl to improve irradiation reproducibility. Supportive and Palliative Cancer Care, 2, 71–75.
To evaluate the compliance to radiation treatment planning of patients with bone metastases who have been premedicated with transdermal fentanyl
Intervention Characteristics/Basic Study Process:
Fentanyl was delivered at 25–50 mcg/hour starting a week before treatment planning and during simulation. Immobilization devices were not mandatory.
- The sample was composed of 42 enrolled patients.
- Mean patient age was 68.5 years.
- Of all patients, 16 were male and 26 were female.
- Patients had epithelial cancer with skeletal metastases and strong pain uncontrolled by FANS and/or steroids. The most common primary cancers were breast and prostate cancers. All patients had 1–4 metastatic bone sites.
- Median pain score at first evaluation was 12 (the range of scores was 4–36), mean Karnofsky Performance Status Score was 60 (range, 40–80). In the sample were 47 treated metastases: 27 vertebral bodies, 11 of the femur, 3 of the humerus, and one of the pelvis.
- Patients were excluded if they had bone fractures or spinal cord compression; if estimated life expectancy was longer than three months; or if they did not have brain metastases.
- Pretreatment measures included physical examination; bone scan; x-ray; CT and/or MR scan; and Karnofsky Performance Status Score, with special emphasis on pain
- Modified Radiation Therapy Oncology Group (RTOG) scale (including domains measuring severity and frequency of pain and use of analgesic drugs), to measure modified pain
- Spitzer Quality of Life Index, or QL-I (0–10, with 10 being best quality of life), to measure quality of life
- Primary endpoint: patients’ compliance to maintaining established position
- Secondary endpoint: quality of life at end and at 40 days after external-beam radiation therapy
- Median pain score at treatment planning was 8 (range, 3–36).
- During simulation, 39 of 42 patients maintained position throughout the entire treatment period.
- The day after first external-beam radiation therapy, median pain score was 8. Median QL-I of 35 of 42 patients was 5 (range, 2–9).
- At end of treatment, pain score median was 6 (range, 1–36), QL-I was 6 (range, 2–10).
- Two patients died within 40 days of the end of radiation therapy.
- At 40 days after radiation therapy, median pain score of 40 patients was 3.5 (range, 0–24) and median QL-I score of 33 patients was 7 (range, 2–10).
- Treatment with fentanyl was well tolerated. The most common adverse responses were nausea, vomiting, constipation, and dizziness.
- According to the treating physician, 95% of patients maintained best position. This result suggests that patients’ comfort was acceptable.
- The intervention resulted in amelioration of quality of life for all patiients at end of radiation therapy and at 40 days after completion of therapy.
Transdermal fentanyl is efficacious and associated with minimal side effects.
- The study had a small sample size.
- Other factors affecting pain, such as use of analgesics, were not clearly defined. The scale accounted for such use in a general way but not specifically.
- Authors did not identify the specific drug being studied.
- During pain assessment, what was the site of pain? Was it at the site of metastasis or elsewhere?
- The treating physician decided whether a patient maintained the position. The report mentioned no quantitative measure associated with compliance.
- Were patients mobile? Where they at home or in an inpatient or hospice setting?
Previous studies have shown that perception of improved quality of life positively influences duration of survival.
Tassinari, D., Sartori, S., Tamburini, E., Scarpi, E., Raffaeli, W., Tombesi, P., & Maltoni, M. (2008). Adverse effects of transdermal opiates treating moderate–severe cancer pain in comparison to long-acting morphine: A meta-analysis and systematic review of the literature. Journal of Palliative Medicine, 11(3), 492–501.doi: 10.1089/jpm.2007.0200
To compare the safety profiles, adverse effects, and patients' preferences regarding slow-release oral morphine and transdermal opiates
- Databases searched were MEDLINE and EMBASE, January 1966–June 2006.
- Search keywords were administration, cutaneous (in subject headings); analgesic, opioid/*administration, and dosage adverse effects (in subject headings); and fentanyl, buprenorphine, cancer pain/*drug therapy (as main terms).
Studies were included if they
- Were randomized controlled trials at phase III.
- Included subjects with moderate to severe cancer pain and who had a defined opiate need at study entry.
- Compared slow-release oral morphine to transdermal opiates.
- Studies were excluded if information about randomization was inadequate, the study did not report safety data, the sample included patients who needed opiate titration at study entry, or the study used historical controls or was a phase 2 trial.
- The search retrieved 117 studies. Twelve studies were considered potentially eligible. Four were included in analysis.
- Authors evaluated study quality by means of the Jadad scale. Two of the studies were of low quality, with a Jadad score of 2 or less.
- The sample for meta-analysis consisted of four studies, which included 425 patients. Of the 425 patients, 188 were treated with transdermal fentanyl and 26 received buprenorphine.
- The range of sample size was 47–202 patients.
- Comparison of overall adverse effects showed no heterogeneity and no difference between treatments (odds ratio [OR] 0.789, p = 0.465).
- Compared to oral slow-release morphine, transdermal opiates seemed better at reducing constipation (OR = 0.38, p < 0.001). Authors noted no differences or heterogeneity in other adverse events.
- Authors analyzed adverse events overall as well as individually. Adverse events included constipation, diarrhea, anorexia, nausea, vomiting, insomnia, somnolence, confusion, headache, and vertigo.
- Patient preference data showed that patients favored transdermal opiates (OR = 0.43, P = 0.014).
Compared to slow-release oral morphine, transdermal opiates were associated with fewer cases of constipation. Patients tended to prefer transdermal opiates to slow-release formulations.
- This meta-analysis had a small sample size.
- Of the four studies in the meta-analysis, the quality of two studies was low. View findings with caution.
Compared to slow-release oral morphine, transdermal opiates appear to be associated with fewer cases of constipation; transdermal opiates may be a better alternative for pain control in patients with constipation. This review suggests that patients may prefer pain medication via the transdermal route. Clinicians should consider constipation and preference in individualizing pain management.
Wootten, M. (2004). Morphine is not the only analgesic in palliative care: Literature review. Journal of Advanced Nursing, 45(5), 527–532.doi: 10.1046/j.1365-2648.2003.02936.x
DATABASES USED: CINAHL and MEDLINE
KEYWORDS: Cancer pain, pain management, and morphine; reference list from search articles 1990–2000
INCLUSION CRITERIA: Only articles using strong opioids (e.g., morphine, methadone, ketamine, fentanyl)
COMMENTS ON LITERATURE USED: Most articles were anecdotal or case studies. A total of 16 articles fit inclusion criteria.
FINAL NUMBER STUDIES INCLUDED = 16
KEY SAMPLE CHARACTERISTICS: Patients with cancer using strong opioids; no true sampling
The evidence does show encouraging results with use of fentanyl, methadone, and ketamine. Transdermal fentanyl is recommended for those with stable pain because it is difficult to titrate quickly. All of these strong opioids were well tolerated and seemed to be comparable to morphine.
Most of the evidence available is anecdotal.
More research is needed in this area.