Article Text


How practical are transmucosal fentanyl products for breakthrough cancer pain? novel use of placebo formulations to survey user opinion
  1. Ruth England,
  2. Matthew Maddocks,
  3. Cathann Manderson,
  4. Sonja Zadora-Chrzastowska and
  5. Andrew Wilcock
  1. Hayward House Macmillan Specialist Palliative Care Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK
  1. Correspondence to Dr Andrew Wilcock, Clinical Reader in Palliative Medicine and Medical Oncology, Honorary Consultant Physician, Macmillan Specialist Palliative Care Unit, University of Nottingham, Nottingham University Hospitals NHS Trust, Hayward House, Nottingham NG5 1PB, UK; andrew.wilcock{at}


Background Three transmucosal fentanyl products have recently been licensed for cancer-related breakthrough pain: a sublingual tablet, a buccal/sublingual tablet and a nasal spray. Limited comparative data hinder identifying the most appropriate to use and adopt onto a service formulary. However, the availability of placebo formulations provides a unique opportunity to compare the practical aspects of their use.

Methods 30 patients with cancer accessed and administered a placebo of each product and were asked to rate them using 1–7 Likert agree–disagree scales and free-text responses, with regard to ease of access and administration, palatability and overall impression. Participants rated their usual rescue analgesic similarly, based on recall. They also indicated whether they would be prepared to use the fentanyl product, and their most preferred.

Results For accessibility, the usual rescue analgesic was rated best (median score 3), significantly better than the buccal/sublingual tablet (p=0.01) and nasal spray (p<0.01), but not the sublingual tablet. Conversely, the nasal spray was rated significantly worse (median score 7) than the others (p<0.01). For ease of administration, the usual rescue analgesic and sublingual tablet were rated equally best (median score 1), with only the latter being significantly different to the buccal/sublingual tablet (p=0.04) and nasal spray (p=0.05). For palatability, the sublingual tablet was rated the best (median score 2), but was significantly different only to the buccal/sublingual tablet (p<0.01). For overall impression, the sublingual tablet was rated significantly better (median score 3) than the others, with more patients prepared to use it and selecting it as their most preferred (27 and 18, respectively).

Conclusion This survey provides valuable insight into the practical aspects of these three transmucosal fentanyl products for practitioners considering their use.

View Full Text

Statistics from


Cancer breakthrough pain often rapidly becomes severe and generally lasts less than 30 min.1 2 Thus, medication given orally, for example, morphine, has the potential disadvantage of taking too long to work and of causing unwanted effects beyond the duration of the pain episode.3 In an attempt to overcome these drawbacks, three fentanyl-based products, administered as a tablet sublingually4 or buccally/sublingually5 or as a nasal spray,6 have recently gained marketing authorisations for cancer-related breakthrough pain in several countries. They are similar in cost (about £5 (US$8) per dose), are more effective than placebo, but have not been directly compared with orally administered analgesics or with each other in patients with cancer.7 Such comparison is limited to the buccal/sublingual tablet and oxycodone in patients with chronic non-cancer pain.8 This makes selecting the most appropriate product to use difficult. However, placebo versions are provided by the companies for patient education. This provided an opportunity to obtain service users’ opinion on the practical aspects of use of the products, to help inform our considerations around which, if any, to recommend for local formulary adoption.



Having confirmed that ethical approval was not required, the survey was registered as a service improvement project with the Audit and Clinical Effectiveness Department (No. 543). Patients attending day care at a specialist palliative care unit who were receiving strong opioids for background and breakthrough episodes of cancer pain were approached. It was explained to these patients that their opinion about the practical aspects of the use of three new analgesic products, which begin to act within 10–15 min, was being sought; it would involve trying a placebo of each; there was no obligation to take part; the results would be anonymised and shared with others.


For descriptive and comparative purposes, participants’ use of different routes of drug administration and experience with their current rescue analgesic were noted. Based on recall, this included the time taken to achieve meaningful pain relief (as defined by the participant) and ratings of the following aspects: the ease with which a dose can be accessed from its container and administered, palatability (based on taste and other sensations) and overall satisfaction (taking into account efficacy and tolerability). Responses were recorded on a 1–7 Likert agree–disagree scale, with scores of 1, 4 and 7 representing extreme positive, neutral and extreme negative responses, respectively. Verbal descriptors on the scale varied with the aspect being rated, that is, ranging between definitely easy–definitely difficult (accessibility and administration), definitely like–definitely dislike (palatability) and definitely satisfied–definitely unsatisfied (overall satisfaction). Free-text comments were also invited.

Participants were then given a placebo of each product and asked to access and administer it, having been given standardised written and verbal instructions as per the product literature. The order of presentation was randomised but balanced so that each product was presented first, second or third to the same extent. The placebos were packaged identically to the active products: the sublingual and buccal/sublingual tablets in strips, and the nasal spray bottle in a childproof plastic box. As per normal practice, participants could place the buccal/sublingual tablet placebo either buccally or sublingually. The mouth was cleansed with water in between, and the time taken to achieve complete dissolution for the sublingual and buccal/sublingual placebos was noted by a stopwatch. Following use of each placebo, participants rated the same pragmatic aspects and, because analgesic efficacy was not being assessed, their overall impression (ranging between definitely like and definitely dislike), taking all of the practical aspects into account. Participants were also asked to indicate whether they would be prepared to use the product and, after all three had been tried, to identify which, if any, they preferred most.

Statistical analysis

Data were expressed as mean and SD or median and IQR as appropriate. A Kruskal–Wallis test was used to examine for the effect of the product on ratings of accessibility, administration, palatability and overall impression and the Mann–Whitney test with a Bonferroni correction for post-hoc paired comparisons between products. Calculations were performed using SPSS (V.16) and a p value of ≤0.05 was considered statistically significant. The sample size reflected the number of patients recruited over a 3-month period.


Participant details

Of 59 patients approached, 30 took part; they had a mean (SD) age of 65 (8) years and 15 were male. All had taken drugs by mouth, and 11, 6 and 2 had used the nasal, sublingual and buccal routes respectively. Current rescue analgesia consisted of solution or tablet formulations of morphine (22) or oxycodone (7), with one using subcutaneous morphine. Median (IQR) reported time to achieve meaningful pain relief was 30 (20–30) min. The median overall level of satisfaction with current rescue medication was ‘moderate’ (score of 2; table 1). Of the 12 free-text comments made, 8 were negative, with 4 relating to the time taken to obtain pain relief.

Table 1

Median (IQR) ratings for the practical aspects of using usual rescue analgesic and a placebo of each of the fentanyl products together with overall satisfaction or impression


The usual rescue analgesic was rated best (median score 3, ‘mildly easy’), which was significantly better than both the buccal/sublingual tablet and the nasal spray (p=0.01, <0.01, respectively), but not the sublingual tablet. Of the placebos, there was no difference between the sublingual and buccal/sublingual tablets (median scores 5, ‘mildly difficult’), but the nasal spray received the worst rating (median score 7, ‘definitely difficult’), which differed significantly from the others (p<0.01 for both) (table 1).

With the usual analgesic, eight participants reported difficulties, for example, removal of childproof caps and using a spoon for liquid formulations. Despite instruction, 2, 5 and 17 participants required assistance in opening the sublingual tablet, buccal/sublingual tablet or nasal spray placebos respectively. Difficulties with access led one to refuse to take the buccal/sublingual tablet.

Ease of administration

The usual rescue analgesic and the sublingual tablet were rated equally best (median score 1, ‘definitely easy’) while both the buccal/sublingual tablet and nasal spray received a median score of 2, ‘moderately easy’ (table 1). This difference was significant between the sublingual tablet and buccal/sublingual tablet (p=0.04) or nasal spray (p=0.05).

Eighteen and eleven participants chose to place the buccal/sublingual tablet sublingually or buccally respectively. For the sublingual and buccal/sublingual tablets, the median (IQR) time to dissolution was 57 (37–72) s and 323 (186–443) s respectively, generating 20 positive comments relating to the convenience of the sublingual tablet and 18 negative ones for the buccal/sublingual tablet. Four participants were uncertain about the placement of buccal/sublingual tablet when used buccally, and one had difficulty keeping the sublingual tablet under the tongue. Generally, those with prior experience of the nasal route found the placebo nasal spray easier to administer. One patient reported being unable to tell whether a dose of the nasal spray had been received.


The sublingual tablet was rated the best with a median score of 2 ‘moderately like’, and this was reflected in 12 positive comments relating to a lack of taste and rapid dissolution (table 1). The difference was significant only between the sublingual and buccal/sublingual tablets (p<0.01). Ratings for the usual analgesic and remaining placebos were all neutral, but there were mixed comments regarding the taste (usual analgesic, buccal/sublingual tablet) and sensation of effervescence (buccal/sublingual tablet). Eight participants disliked the taste of their usual analgesic, whereas two liked it. The taste of the sublingual/buccal tablet was disliked and liked by seven and five participants, respectively. The sensation of effervescence with the buccal/sublingual tablet generated two negative and two positive comments. Participants reported no taste or smell with the nasal spray.

Overall impression, prepared to use and most preferred

For ‘overall impression’, the sublingual tablet was rated significantly higher (median score 3, ‘mildly like’) than the buccal/sublingual tablet (p<0.01) and nasal spray (p=0.04) placebos (median scores both 4, ‘neither like nor dislike’) (table 1). Twenty-seven, 18 and 17 participants indicated that they would be prepared to use the sublingual tablet, buccal/sublingual tablet and nasal spray products, respectively. For their most preferred product, 18, 6 and 2 chose the sublingual tablet, nasal spray and buccal/sublingual tablet respectively. Three chose none because of inability to open any of the products, disliking all the products or being unable to choose between the sublingual and the buccal/sublingual tablets. Free-text comments identified themes that explained these choices: the sublingual tablet was popular because of the relative ease of access, lack of taste and speed at which it dissolved; 12 participants reported that they would refuse the nasal spray based solely on the difficulty encountered in opening the childproof box; compared with the sublingual tablet, the buccal/sublingual tablet was relatively more difficult to access and took longer to dissolve.


This survey used placebo forms of three transmucosal fentanyl products for breakthrough cancer pain to ask service users to compare the practical aspects of their use. Despite verbal and written instruction as provided by the manufacturers, a number of differences emerged with regard to accessibility, administration and palatability. Relative to the other placebos, overall, the sublingual tablet was generally easier to access, administer and more palatable. Consequently, more participants indicated that they would be prepared to use this product and rated it as their most preferred product.

In addition to identical packaging, the companies claim that the placebos provide the same experience as the actual products with regard to speed of dissolution, taste or nasal tolerability. Thus, our assessment of accessibility, administration and palatability should be valid, as also overall impression, preparedness to use the product and most preferred arising from these considerations.

Current rescue analgesics performed reasonably well in comparison with the new products, in particular in relation to ease of access and administration. Overall, participants were moderately satisfied with their usual medication and this could have influenced their impressions of the new products. Nonetheless, about one-tenth of participants were unhappy with the length of time it took to obtain pain relief with their usual rescue analgesic. Formal comparison in this patient group is required to confirm whether these three fentanyl products can successfully address this.

Limitations of this survey include the relatively small sample size and that the ratings for current rescue analgesics were based on participants’ recall rather than prospective evaluation. The assessors were not blinded to the products being administered, which could introduce bias. However, both written and verbal instructions were standardised according to product literature, and none of the fentanyl products were already on the departmental formulary. Further, the use of placebos meant that we could not assess the analgesic efficacy and compare overall satisfaction with the new products. A similar formal study, although technically possible, would be prohibitively complex, in part because of the need to individually dose titrate and blind each product.

This is a rapidly changing area, and since undertaking our survey, another fentanyl nasal spray9 has obtained market authorisation, with others in development. The availability of placebo versions would permit similar surveys to be undertaken. We did not compare a placebo of the lozenge on a stick formulation,10 as this is already on our hospital formulary.

In conclusion, the involvement of service users in this survey has provided valuable feedback, which will help inform our formulary decision making locally and may also be of interest to other practitioners considering using these products.


We would like to thank the participants of this survey.


  1. 4.
  2. 5.
  3. 6.
  4. 7.
  5. 8.
  6. 9.
  7. 10.
View Abstract


  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.