Postoperative pain relief following pancreaticoduodenectomy: Triple P (PostPainPan) Study

Pancreaticoduodenectomy (PD) is the treatment of choice for a myriad of (non-)
malignant diseases of the pancreas, duodenum and periampullary region. PD is
performed under general anesthesia and in a restricted number of hospitals in
the Netherlands.In this procedure the head of the pancreas and part of the
duodenum are removed. There are various methods for postoperative pain control
with varying levels of postoperative pain scores and patient satisfaction.
Result from the Leids Universitatir Medisch Centrum (LUMC) show that the
percentage of PD patients with a postoperative pain score > 4 (on an 11-point
scale from 0, no pain to 10, most extreme pain imaginable) for patients that
received an epidural analgesia (EA) and those that received another form of
postoperative pain treatment (most importantly intravenous patient controlled
analgesia with morphine) differ from each other. While the percentage of
patients not receiving an epidural had higher pain scores on day 0 (day of
surgery), the opposite was true on day 3-4, the percentage was higher for
patients that had received an epidural. For patients treated with intravenous
patient controlled analgesia with morphine, initial pain score where high and
later pain scores were low.

In Europe a new form of pain treatment has become available since 2 years,
namely postoperative sublingual sufentanil tablets (SST). SST consists of
patient-controlled had held device that delivers 15 mug sufentanil
micro-tablets at a minimum of 20 min interval. It is currently used as standard
of care in multiple hospitals in the Netherlands. In a recent retrospective
cohort analysis of 300 patients of patients from several hospitals in the
Netherlands including LUMC, Reinier de Graaf Hospital and Maasstad Hospital, we
observed low average pain scores following SST treatment in patients after
large abdominal and orthopedic surgery (70% of patients with a pain score < 4
on the first postoperative day). We relate this to the pharmacokinetic and
pharmacodynamic properties of sublingual sufentanil. The drug is highly
lipophilic and is rapidly absorbed after which it passes the blood-brain
barrier within minutes (t*ke0 about 6 min). Due to the sublingual formulation
peak concentrations are relatively low and consequently, concentration
dependent side effect -such as acute respiratory depression- do not occur. Due
to its rapid onset of action, there is little delay in pain relief between the
moment of administration and the onset of pain reduction. Hence, we like to
ascertain the lack of disadvantage, i.e. non-inferiority of SST versus
intravenous patient controlled analgesia with morphine or EA in our population
of PD patients. We will thereto compare the pain data obtained from these three
standardized pain treatments in our hospitals in pancreaticoduodenectomy
patients.

- Primary objective: To compare the efficacy of postoperative pain treatments
with sublingual sufentanil micro-tablets versus intravenous patient controlled
analgesia with morphine or epidural analgesia in patients following
pancreaticoduodenectomy in terms of pain intensity and patient satisfaction.
- Secondary objectives: To compare outcome parameters between treatment groups.

This is an investigator-initiated, open-label, strategy, randomized controlled
trial in which patients will be randomized to receive either an (epidural
catheter prior to surgery for postoperative pain treatment or intravenous
patient controlled analgesia with morphine) or the sublingual sufentanil system
postoperatively.

The anesthetics (type and dose) given during general anesthesia will be left to
the discretion of the attending anesthesiologist and/or resident.
Patients randomized to the epidural group will receive an epidural catheter
according to local protocol. At LUMC, following induction the epidural
analgesic medication will be administered (ropivacaine 0.75%) as bolus 6-12 mL
followed by a continuous infusion (ropivicaine 0.2%/sufentanil 0.75 mug/mL;
6-10 mL/h; with the possibility of giving an additional bolus). In the PACU
(recovery/ward) pain will be assessed using the 11-point numerical rating scale
(NRS; from 0, no pain to 10, most extreme pain imaginable) at regular
intervals. In case of pain score > 4, epidural bolus infusions will be
permitted and the patient controlled epidural analgesia (PCEA 1-2 mL bolus,
20-min lockout) system will be started according to local protocol.
Additionally, all patients will receive 4 times daily paracetamol 1000 mg and
an NSAID/metamizol if allowed according to local protocol.
Patients randomized to the SST will receive long-acting intravenous opiates
(e.g. morphine) prior to the end of surgery. In the PACU pain will be assessed
using the 11-point numerical rating scale (NRS; from 0, no pain to 10, most
extreme pain imaginable). In case of pain score > 4, an opiate will be given
according to local protocol. When pain scores are 4 or less, the SST system
will be started. Additionally all patients will receive 4 times daily
paracetamol 1000 mg ± an NSAID/metamizol 3 times daily.
In case of insufficient pain relief during the course of treatment, patients
may receive rescue pain relief according to local protocol, i.e. conversion to
IV PCA Morphine or to EA; if this does not help, IV ketamine is added (up to 10
mg/h).
After 3-6 days postoperatively both the SST system and the epidural will be
terminated and replaced by naproxen/NSAID, paracetamol, an oral or subcutaneous
opiate depending on the pain score (and local protocol). At LUMC:
- NRS < 4: paracetamol 4 times daily 1000 mg + naproxen 500 mg 3 times daily;
- NRS 4-6: oxynorm 5 mg p.o. (max. 6 times/day), combined with to paracetamol ±
NSAID as mentioned above;
- NRS > 6: morphine s.c. up to 20 mg (max. 6 times/day), combined with to
paracetamol ± NSAID as mentioned above.

Negligible burden and risks are expected. Possible disadvantages can easily be
treated.