J. Maxillofac. Oral Surg.

(2024) 23:552–560
https://doi.org/10.1007/s12663-022-01713-6

ORIGINAL ARTICLE

Comparaison of Efficacy and Safety of Fentanyl Transdermal

Patch with Oral Ketorolac for Pain Management in Dry Socket:
A Randomized Clinical Trial
Abid Majeed Rather1 • Sachin Rai1 • Vidya Rattan1 • Satnam Singh Jolly1 •

Samir Malhotra2

Received: 31 January 2022 / Accepted: 21 March 2022 / Published online: 18 April 2022
Ó The Association of Oral and Maxillofacial Surgeons of India 2022

Abstract on all follow-up days. Significant difference was noted in

Objectives The aim of this study was to compare the the mean amount of rescue analgesic medication. It was
efficacy and safety of transdermal Fentanyl patch with oral 2.16 ? 1.53 in group 1 and 8.50 ? 3.98 in group 2. Side
Ketorolac for pain management in dry socket patients. effects were seen in both the groups. Nausea (46%) and
Study design Sixty patients who were diagnosed with dry vomiting (43%) were reported in group 1 while headache
socket (VAS [ 40 mm) were recruited in this prospective (36.6%) and epigastric pain (53.3%) in group 2.
randomized controlled trial. Patients were divided into two Conclusions Thus, transdermal Fentanyl was better in pain
groups. Group1 (n = 30) Transdermal Fentanyl patch control than Ketorolac with less need for rescue analgesic
(25mcg/hr) was given and in Group 2 (n = 30) Ketorolac medication in dry socket.
10 mg Oral tablet was prescribed for pain management.
The primary endpoint was the mean pain scores within Keywords Dry socket
Alveolar osteitis
Ketorolac

72 h evaluated by visual analog scale (VAS). Secondary Fentanyl
Transdermal drug delivery
measures included the safety and tolerability, amount of
rescue medication (analgesic and antiemetic) and effec-
tiveness of treatment interventions by Brief Pain Inventory Introduction
Questionnaire (BPI).
Results The mean VAS pain scores were significantly less Dry socket or alveolar osteitis is an undesirable and
in group 1 (Fentanyl) as compared to group 2 (ketorolac) extremely painful complication after extraction of teeth [1].
The routine treatment modalities for pain management
include local anaesthetic agents, placement of intra socket
& Abid Majeed Rather medicaments and local antimicrobials [2–5]. Although
drabidr8@gmail.com various secondary complication like bone necrosis, foreign
Sachin Rai body reactions, delayed wound healing and neuritis, etc.,
drraisachin@gmail.com have been seen with the use of local measures like Zin
Vidya Rattan oxide eugenol (ZOE) [6].Newer modalities include appli-
drvidyarattan@gmail.com cation of low level laser therapy and plasma-rich growth
Satnam Singh Jolly factors in the socket [7, 8] but still there is lack of con-
satnamsurgeon@gmail.com sensus with no strong evidence advocating any particular
Samir Malhotra method for pain management..
smal.pgi@gmail.com Potent non-steroidal anti-inflammatory drugs (NSAIDs)
1 like Diclofenac or Ketorolac are commonly used analgesic
Unit of Oral and Maxillofacial Surgery, Oral Health Sciences
Centre, Postgraduate Institute of Medical Education and after extraction of teeth but are known for various adverse
Research, Chandigarh, India effects like epigastric pain, peptic ulceration/ bleed, dys-
2
Department of Pharmacology, Postgraduate Institute of pepsia, renal damage and prolonged bleeding time [9–11].
Medical Education and Research, Chandigarh, India Opioids have been found to be more potent in severe tooth

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J. Maxillofac. Oral Surg. (2024) 23:552–560 553

pain due to central and peripheral effects on pain receptors (Ketorolac). Each group was divided into two age group
[12–14]. However, oral opioids have various disadvan- (18–40 years & 41–60 years) with 15 patients in each
tages, e.g. nausea, short half-life that needs multiple doses, subgroup (Table 1). Computer generated list was prepared
inadequate analgesia during break through pain periods, and age stratified block randomization was done. Sequen-
less patient compliance, first pass metabolism and opioid tially numbered opaque sealed envelopes were used for the
addiction. [15–17]. allocation of patients in the respective groups.
To overcome these disadvantages, Fentanyl which is a
potent opioid agonist was approved by FDA as a trans- Procedure
dermal patch, in 1995. It is now being widely used for pain
management in cancer patients and pain control after The Diagnosis of the dry socket was made by clinical
orthopaedic, gynaecological and ophthalmic surgeries, etc. history of persistent throbbing pain (VAS 40 mm) between
[18–21] It is available as a patch with various concentra- 24 and 72 after extraction of teeth that was radiating to
tions of fentanyl 12.5, 25 and 50 lg/hr with variable head and neck regions and also with other signs and
therapeutic window among population [22]. Fentanyl patch symptoms like halitosis, foul taste along with presence of
releases the drug at a nearly constant rate and provide localised swelling and extraction wound devoid of blood
higher therapeutic drug concentration and better analgesia clot on clinical examination [5]. Preoperative radiographs
as compared to oral NSAIDS and opioids [19, 23, 24]. of extraction sockets were taken to rule out any remaining
Keeping in view the advantages of transdermal drug root piece or loose bone. A pre-treatment pain evaluation
delivery system over oral drugs, we hypothesized that it by visual analog scale (VAS) and Pain severity and pain
can be used as an effective treatment modality for pain inventory scores by modified brief pain inventory ques-
management of dry socket. The aim of this study was to tionnaire (BPI) in English and Hindi languages was done
compare the efficacy of Fentanyl transdermal patch in and the patients were then allocated to their respective
comparison to oral Ketorolac for pain management in dry treatment groups [18, 25–27]. Measurement of post-treat-
socket. ment pain was done on each morning and evening for six
consecutive days by patients on pain dairy with imprinted
VAS pain scale given to each patient in both groups.
Patients and Methods Fentanyl group patients received 25 lg/hr Fentanyl
transdermal patches on intact hairless skin on (Deltoid or
Study Design scapular region) with date and time of the patch application
mentioned for 72 h. The patients were monitored for 72 h
The study was conducted from August 2019 to October after patch application for any complication and second
2020. It was an active controlled open label, randomized patch was placed only in those patients in which pain
clinical trial with 1:1 allocation of patients in both the persisted with a VAS score of [ 40 mm after third post-
groups. The study was approved by Institutional Ethical intervention day. A total of 2 fentanyl patches were applied
Committee and consent was taken from every patient depending on need of patients. The assessment of relieve in
before intervention. The study was registered with Clinical pain scores after second patch placement was seen by VAS
Trials Registry-India (CTRI), Reg. No: CTRI/2020/02/ score on 6th post-intervention day. Tab Ondansetron 8 mg
023538 and was done following the CONSORT guidelines. was given prophylactically in fentanyl group patients to
(Fig. 1: CONSORT Flow Diagram) A total of 60 patients prevent nausea and vomiting which is a common side
within the age range of 18–60 years of either sex who were effects of opioid’s [18]. Ketorolac group patients were
diagnosed with dry socket or post extraction pain given Tablet Ketorolac, first 20 mg of loading dose on day
(VAS [ 40 mm) were recruited. Patients allergic to Fen- 1 followed by 10 mg thrice daily for six consecutive days,
tanyl or Ketorolac, women during their menstrual cycle, representing a control regimen.
pregnant and lactating mothers. Those with intra oral Paracetamol were given as a rescue analgesic medica-
infection/abscess, history of GIT problems, or having tion in both the groups, and the number of pills taken by
migraine, severe asthma, ulcerative or malignant lesions patients were noted. Patients who felt persistent pain even
and alcoholic or narcotic abusers were excluded from the after drug intervention were given Zinc Oxide Eugenol
study. (ZOE) dressing in the extraction socket as rescue medica-
tion. Saline irrigation of the extraction (dry) socket and
Sample Size Calculation patient evaluation for side effects were done on 1st, 2nd,
4th and 6th post-treatment day in both the groups. Safety
A convenient sample of 60 patients were randomly and side effects in both groups were seen by comparing
assigned (30 each) in Group 1 (Fentanyl) and Group 2 number of episodes of nausea, vomiting, headache,

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Fig. 1 CONSORT Flow

Diagram

somnolence, local site reaction, constipation and epigastric Statistical Analysis

pain.
At the follow-up day 10 all the patients were given the The results were analysed by using SPSS version 18.
BPI questionnaire again to evaluate the pain parameters Results on continuous measurements were presented on
like pain severity score and pain interference score after the Mean ± SD (Min–Max) and on categorical measurements
treatment intervention in both the groups to see the effec- in Frequency (Percentage). Normality of the data was
tiveness of the treatment on the pain severity and its effect assessed using Shapiro–Wilk test and Chi-square test/Fis-
on general activities of life. [25–27]. cher exact test, Mann–Whitney U test was used to check
difference between the groups. Wilcoxon signed-ranked
sum test was used to check difference within a group over a
period of time.

Table 1 Demographic data

Age (Years) Fentanyl (N = 30) n (%) Ketorolac (N = 30) n (%) p-value
(Mann Whitney U testa, Chi-
squared testb) 18–40 15 (50) 15 (50) 0.791a
41–60 15 (50) 15 (50)
Mean ± SD 40.63 ± 11.62 41.63 ± 9.15 0.959a
Gender
Females 15 (50) 19 (63.33) 0.297b
Males 15 (50) 11 (36.66)
Homogenous and comparable for age and gender distribution

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p value less than 0.05 was considered to be significant. in Fentanyl group from baseline to day six as compared to
Ketorolac group (p = 0.001) (Table 3).
The requirements of rescue analgesic medication were
Results more in the Ketorolac group as compared to Fentanyl
group on all follow-up days which was statistically sig-
The mean pain scores at baseline (Day 1 morning) were nificant. Rescue antiemetic medication was only needed in
comparable (p = 0.297) in both the groups (Fentanyl and Fentanyl group mean ± S. D (0.56 ± 1.30) with maxi-
Ketorolac group). The mean pain scores (VAS mm) mum amount needed on Day 2 (p \ 0.005) (Table 4).
decreased significantly in both the groups on all post-in- Significantly high percentage of vomiting and constipation
terventions follow-up days but, significant decrease was occurred in Fentanyl Group, whereas epigastric pain was
seen in the Fentanyl group as compared to ketorolac group seen more in Ketorolac group (Table 5).
(p = 0.001) (Table 2) (Fig. 2). On comparison of inter-in- On comparison of pain evaluated by BPI questionnaire,
terval VAS difference between the two groups statistically there was statistically significant decrease in both pain
significant increase in the mean pain differences was seen severity and pain interference scores from baseline

Table 2 Comparison of Pain Scores at different follow-up days. (Mann Whitney U test)
Follow up Fentanyl group (Mean ± SD) VAS (mm) Ketorolac group (Mean ± SD) VAS (mm) P value

Baseline (D1M) 70.36 ± 14.95 74.86 ± 15.77 0.297

Day 1E 52.33 ± 21.28 64.60 ± 18.84 0.021*
Day 2 M 29.86 ± 24.09 61.13 ± 19.79 0.001*
Day 2E 23.60 ± 23.20 56.56 ± 19.85 0.001*
DAY 3 M 15.26 ± 16.27 57.50 ± 22.26 0.001*
Day 3E 12.06 ± 15.80 53.86 ± 23.37 0.001*
Day 4 M 12.10 ± 18.24 52.43 ± 21.33 0.001*
Day 4E 11.10 ± 14.64 45.90 ± 22.25 0.001*
Day 5 M 8.33 ± 9.48 42.66 ± 23.14 0.001*
Day 5E 6.33 ± 7.22 35.46 ± 21.63 0.001*
DAY 6 M 4.90 ± 6.00 29.63 ± 18.85 0.001*
Day 6E 4.86 ± 7.66 27.46 ± 21.35 0.001*
*Significant (M = Morning E = Evening)
Inference Statistically significant differences were observed

Fig. 2 Figure showing

comparison of mean VAS (mm)
between groups

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Table 3 Inter interval analysis

Group Baseline day Follow up day VAS (mm) (Mean ± SD) P value
within groups (Wilcoxon signed
ranked sum test) Fentanyl D1M (Baseline) D1E 18.03 ± 13.07 0.001*
D2 43.63 ± 16.08 0.001*
D3 56.70 ± 17.01 0.001*
D4 58.76 ± 18.13 0.001*
D5 63.03 ± 15.64 0.001*
D6 65.48 ± 16.93 0.001*
Ketorolac D1M (Baseline) D1E 10.26 ± 16.56 0.003
D2 16.01 ± 16.36 0.001*
D3 19.18 ± 21.55 0.001*
D4 25.70 ± 18.03 0.001*
D5 35.80 ± 19.58 0.001*
D6 46.31 ± 21.16 0.001*
Inference Statistically significant differences were observed

Table 4 Comparison of mean

Rescue Medications Fallow up day Fentanyl (Mean ± SD) Ketorolac (Mean ± SD) P value
amount of rescue analgesic and
antiemetic medication intake Analgesic medication Day 1 1.26 ± 0.78 1.93 ± 0.90 0.003*
between groups. (Mann
Whitney U test) Day 2 0.40 ± 0.67 1.76 ± 0.77 0.001*
Day 3 0.20 ± 0.40 1.86 ± 1.19 0.001*
Day 4 0.23 ± 0.62 1.46 ± 1.07 0.001*
Day 5 0.06 ± 0.25 0.93 ± 1.08 0.001*
Day 6 0.00 ± 0.0 0.53 ± 0.89 0.001*
Total 2.16 ± 1.53 8.50 ± 3.98 0.001*
Antiemetic medication Day 1 0.03 ± 0.18 0.00 0.317
Day 2 0.26 ± 0.44 0.00 0.003*
Day 3 0.13 ± 0.50 0.00 0.154
Day 4 0.10 ± 0.40 0.00 0.161
Day 5 0.03 ± 0.18 0.00 0.317
Day 6 0.00 0.00 0.99
Total 0.56 ± 1.30 0.00 0.001*
Inference Statistically significant difference was observed between the groups for all days

Table 5 Comparison of side

Side Effects Fentanyl n (%) Ketorolac n (%) P value
effects between the two groups
(Chi-squared test) Nausea 14 (46) 09 (30) 0.287
Vomiting 13 (43.3) 03 (10) 0.008*
Somnolence 2 (6.6) 0 0.470
Dizziness 9 (30) 03 (10) 0.106
Headache 11 (36.6) 16 (53.3) 0.298
Application site reaction 0 0 –
Constipation 11 (36.6) 03 (10) 0.032*
Epigastric pain 3 (10) 11 (36.6) 0.032*
Inference Significant difference was observed for vomiting, Epigastric pain and constipation

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Table 6 Inter group comparison of BPI at baseline and 10 days (Mann Whitney U test)
BPI scores at baseline BPI scores after 10 days
Domain Fentanyl Ketorolac P value Fentanyl Ketorolac P value
(Mean ± SD) (Mean ± SD) (Mean ± SD) (Mean ± SD)

Worst pain 8.50 ± 1.11 8.67 ± 1.37 0.402 1.77 ± 0.63 2.77 ± 1.65 0.004*
Least pain 5.46 ± 1.50 4.93 ± 1.70 0.136 0.40 ± 0.50 1.03 ± 1.45 0.093
Average pain 6.33 ± 1.18 6.27 ± 1.96 0.922 0.77 ± 0.50 1.53 ± 1.14 0.001*
Pain right now 7.06 ± 1.41 7.40 ± 1.52 0.418 0.70 ± 0.60 1.47 ± 1.25 0.004*
General activity 4.6 ± 2.43 5.33 ± 2.68 0.297 0.07 ± 0.25 0.53 ± 0.90 0.009*
Mood 7.03 ± 2.17 7.07 ± 2.80 0.574 2.07 ± 1.05 2.53 ± 1.70 0.469
Walking ability 2.63 ± 1.45 3.27 ± 2.01 0.334 0.03 ± 0.18 0.07 ± 0.25 0.557
Normal work 5.06 ± 1.96 5.33 ± 2.19 0.569 0.37 ± 0.56 0.70 ± 1.17 0.478
Relation with 5.90 ± 2.11 6.30 ± 2.65 0.229 1.20 ± 0.76 1.73 ± 1.48 0.256
people
Sleep 5.06 ± 1.95 6.00 ± 2.26 0.097 1.23 ± 0.68 1.47 ± 1.042 0.509
Enjoyment 6.4 ± 2.11 7.23 ± 2.47 0.093 1.83 ± 0.83 2.40 ± 1.65 0.395
Inference NO significant difference was observed between the groups for BPI Scores at baseline. Significant difference was observed between the
two Groups for some domains (worst, average, current and general activity) of BPI Scores after 10 days

Table 7 Comparison of pain

(Follow-up day) Fentanyl (Mean ± SD) Ketorolac (Mean ± SD) P value
severity scores at different time
intervals (Mann Whitney U test) Pain severity score Baseline 6.71 ± 1.18 6.84 ± 1.37 0.629
10 days 0.90 ± 0.49 1.70 ± 1.33 0.011*
P value 0.001* 0.001*
Pain interference score Baseline 5.23 ± 1.64 5.78 ± 2.09 0.169
10 days 0.97 ± 0.47 1.34 ± 1.06 0.415
P value 0.001* 0.001*
Inference No significant difference was observed between the groups for pain severity score at baseline and
in pain interference score at baseline and 10 days. Significant difference was noted within each group and
in pain severity scores after 10 days between the groups

(mean ± SD) to 10th day in both Fentanyl and Ketorolac Fentanyl patch for pain management in dry socket com-
groups, respectively (p = 0.001) (Table 6). Fentanyl Group pared to oral Ketorolac. The secondary end points were
patients has decreased pain severity score at 10th post- safety and tolerability of drugs evaluated by side effects
intervention day (0.90 ± 0.49) as compared to ketorolac and the need of rescue analgesic and rescue antiemetic
group (1.70 ± 1.33) (p = 0.011). Pain interference scores medications. Placement of transdermal Fentanyl patch in
between the groups at baseline and after 10 days were non- dry socket patients resulted in satisfactory analgesia with
significant (p [ 0.005) (Table 7). 27 out of 30 patients in minimal use of rescue pain medication and less GIT side
group 1 required single transdermal Fentanyl patch, effects and thus can be used as a good option for pain
whereas ZOE pack was placed in 3 patients in the management in this severe condition. [14, 23, 29].
Ketorolac group only. Fentanyl patch provides continuous release of drugs at a
constant rate that provides adequate analgesia and higher
therapeutic drug concentration for management of acute
Discussion and chronic pain. Although this delivery system is not a
new concept, but it seems to have a good potential as well
Dry socket is one of the most common and undesirable as many advantages over oral opioids and NSAIDS for pain
complication seen after dental extractions commonly after control in dry socket. Administration through transdermal
lower molar teeth extractions [1]. Prolonged and severe approach has the advantages of avoiding first half meta-
throbbing pain is not controlled completely even with bolism, constant plasma drug concentrations during
potent NSAIDs [28]. In this novel study the primary breakthrough pain periods, low intestinal absorption issues,
objective was to see the efficacy and safety of transdermal swallowing problems and problems of nausea occurring

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during oral drug intake in some patients and also the ZOE is an easily available and cost effective intra-
incidence of side effects is also less as compared to oral socket medicament to decreases pain in dry socket patients
opioids drugs [19, 23, 24, 29]. Wojciech et al. [15] in a [35]. It was used as an intra-socket medicament in 3
review found transdermally administered opioids are patients in the Ketorolac group when pain was not relieved
characterised by a lower risk of addiction compared to oral even after 6th post-intervention day. All these three
and parenteral routes. [15]. patients had increased VAS scores during the follow-up
In our study, both the groups showed decrease in mean days that caused difficulty for them to do home oral
pain score at 6th day but the difference was high in Fen- hygiene procedures, e.g. brushing, saline rinsing, which
tanyl group. The significant decrease in this group could be lead to delay in healing of extraction socket that caused
due to better control of moderate to severe acute pain by persistent pain even after 6th post-intervention day.
opioids as these drugs have both central and peripheral The need for antiemetic medication was seen only in
effects on pain management as compared to NSAIDS Fentanyl group as opioids are known to cause these main
which act only by inhibiting local mediators of pain and side effects of nausea and vomiting. The indication was
inflammation [30]. The transdermal fentanyl patch drug noted on second postoperative day due to higher plasma
needs 8–12 h to reach peak plasma concentration which concentration of Fentanyl after 24 h which then declines
could be the reason that significant decrease in pain was over time and also tolerance develops to the effects of
seen after 12 h after patch placement [31]. Our study opioids over time. This could be the reason for the maxi-
corroborated with Kim et al. [31] who found that mean mum need of antiemetic for the second post-treatment day
pain scores decreased from baseline to 10 days in painful as compared to other consecutive days. In Ketorolac group,
oral mucositis in haematological cancer patients along with epigastric pain and headache was seen more significantly
safety and tolerability. Todorovic et al. [32] also showed than transdermal Fentanyl. The headache could be due to
that pain was lower in Fentanyl Transdermal System (FTS) referred pain from the extraction socket that was not
group as compared to control regimen in a prospective relieved completely in the Ketorolac patients as compared
study on lower third molar extraction patients. Jokar et al. to Fentanyl. All these side effects were mild and got
[19] also observed less mean pain score after 1 h in case relieved over time by itself.
group (Fentanyl patch) as compared to control group Pain being a multidimensional modality have both
(0.1mcg/kg morphine) in leg fracture patients. sensory and reactive dimensions. So, for its correct eval-
Rescue medication is used to prevent any adverse effects uation and effects on the body, it is important to evaluate
or sub-therapeutic effects of main trial drugs to prevent any all its dimensions. The shorter versions of the BPI have
untoward symptom like nausea, vomiting or pain [33]. The been used in many research and randomized clinical trials
mean amount of rescue analgesic medication (Paracetamol to assess the severity of pain and its interference on various
650 mg) taken was more in the Ketorolac group as com- day to day activities [25–27]. In our study, we also used
pare to Fentanyl group. This could be due to constant drug this scale to assess the two different domains of pain, i.e.
release by the transdermal Fentanyl patch during break the pain severity and its interference with various activities
through pain periods. Similar results were also found by to see the improvement in pain management after drug
Todorovic et al. [32] in a comparative prospective study on interventions. Before intervention, the pain severity and
lower third molar extraction patients (N = 17). Less interference scores in both the groups were statistically
amount of rescue analgesic medications was taken by non-significant, however after 10 days significant
patients in Fentanyl group as compared to control group improvement in both the domains of pain were seen in the
(Diclofenac 75 mg). Matsumoto et al. [20] also in a com- two groups, suggesting that both the drugs decrease the
parative study for postoperative pain management after pain severity and its inference on different activities in dry
knee arthroplasty (N = 52) found less need of recue anal- socket patients. Additionally, the pain severity scores in
gesic medication in Fentanyl group as compared to NSAID Fentanyl group at day 10 were less as compared to
group. Similarly, Bakeer et al. [21] also found less need of Ketorolac group. This could be due to significant steep
additional analgesia in Transdermal Fentanyl group after decrease in pain that encouraged the patients to maintain
breast cancer surgeries. Single transdermal Fentanyl patch good oral hygiene leading to early wound healing and less
was needed in about 90% patients as it had elimination pain compared to Ketorolac group wherein the patients
half-life of about 17 h that lead decreased pain for even were unable to maintain oral hygiene due to constant pain.
more than 24 h after patch removal. [34]. This lead to lodgement of food and debris in the extraction
sockets which decreased wound healing and lead to higher

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