Early Postoperative Administration of Oxycodone +/- Naloxone and Duration of Epidural Analgesia
Early Postoperative Administration of Oxycodone +/- Naloxone and Duration of Epidural Analgesia
Cystectomy with urinary diversion (ileal conduit, ileal orthotopic neobladder, catheterizable
 ileal pouch) is major abdominal surgery, which is associated with a high incidence of
 gastrointestinal complications.Perioperative techniques aiming at an early return of bowel
 function are to be pursued.

 Optimal postoperative pain management is one of the key factors leading to enhanced recovery
 after surgery. The perioperative use of an epidural analgesia for major abdominal surgery is
 established, not only because of its excellent analgesic properties, but also because it can
 accelerate the return of bowel function. However, epidural analgesia is associated with
 additional costs, need for close monitoring and nursing. In addition each supplemental day
 with an indwelling epidural catheter increases the risk of infection. So it is recommended to
 re-assess the risk/benefit ratio of an epidural analgesia after 4 days, if not sooner.
 Therefore, it is important to develop strategies that reduce its duration without impairing
 the benefits. Systemic analgesics with prolonged-release oral formulation like oral oxycodone
 (Oxycontin®) or combined drug mixture (oral oxycodone/naloxone (Targin®)) could be a valuable
 alternative pain treatment as a second analgesic step, starting on postoperative day (POD) 3,
 so that the epidural catheter could be removed earlier without impairing postoperative
 enhanced recovery including return of the bowel function. Both oxycodone and naloxone orally
 administered are a recognized and accepted treatment option.

 The objective of this study is to evaluate the implementation of an oral opioid with or
 without naloxone in the early postoperative period in patients undergoing open radical
 cystectomy with urinary diversion and intraoperative and early postoperative use of epidural
 analgesia. The investigators expect an unchanged early return of the bowel function and equal
 analgesia with a reduced length of stay of the epidural catheter (primary endpoint), thus
 potentially reducing epidural catheter associated complications and lowering costs (nursing
 and pain service).
Background

 Cystectomy with pelvic lymph node dissection and urinary diversion is major abdominal
 surgery, which is associated with a high incidence of postoperative complications.
 Gastrointestinal complications are frequent and perioperative techniques aiming at an early
 return of bowel function are to be pursued.The rationale for this patients population (i.e.
 cystectomy patient with ileal urinary derivation) is that they are at high risk for
 postoperative complications (around 50%) and specially gastrointestinal (8-20%). There is a
 need for improvement in the postoperative setting aiming to reduce complications and costs.

 Optimal postoperative pain management is one of the key factors leading to enhanced recovery
 after surgery. The perioperative use of thoracic epidural analgesia (TEA) for major abdominal
 surgery is established, not only because of its excellent analgesic properties, but also
 because TEA reduces the postoperative stress response, accelerates the return of bowel
 function, and lowers postoperative morbidity and mortality. However, TEA is associated with
 additional costs, need for close monitoring and nursing. Once successfully established, TEA
 requires constant attention from skilled nurses and anaesthetists often from an acute pain
 service to achieve and maintain optimal analgesia. Attention must also be directed to
 limiting or avoiding side-effects such as hypotension or motor block, which will reduce the
 benefits of the technique by preventing the patient from mobilizing effectively after
 operation.In addition each supplemental day with an indwelling TEA catheter increases the
 risk of infection, which is associated with a high morbidity. The mean length of stay of the
 TEA catheter in cystectomy patients at the investigators' institution is 6 days. If the risk
 of epidural infection is low (estimated 1:2000 in Switzerland, this risk increases the longer
 the epidural catheter is left in place. It is recommended to re-assess the risk/benefit ratio
 of TEA after 4 days, if not sooner. Therefore, it is important to develop strategies that
 reduce the duration of TEA without impairing the benefits. Enhanced recovery after surgery
 protocols, which have been established for colorectal surgery in the last 10 years, recommend
 removing the TEA catheter in the morning of postoperative day (POD) 2, which does not impair
 the return of the gastrointestinal function. However, while this approach is well established
 for colorectal surgery, there is less evidence for small bowel surgery or cystectomy with
 urinary diversion.

 Systemic analgesics with prolonged-release oral formulation like oral oxycodone (Oxycontin®)
 or combined drug mixture (oral oxycodone/naloxone (Targin®)) could be a valuable alternative
 pain treatment as a second analgesic step, starting on POD 3, so that the epidural catheter
 could be removed earlier without impairing postoperative enhanced recovery including return
 of the bowel function. Both oxycodone and naloxone orally administered are a recognized and
 accepted treatment option.The selected dosages of both orally administered drugs are in
 accordance with the literature and follow the recommendation of the manufacturers. In
 addition the dosages reflect the clinical practice of the investigators' institution. These
 drugs are daily used in a clinical setting in their pain service. The implementation of a
 placebo controlled group is considered as a gold standard approach in a randomized controlled
 trial aiming to assess the benefit of a drug for a specific indication. In addition, a rescue
 pain medication is implanted in the protocol. Rescue medication for breakthrough pain will be
 additional epidural boluses of 5 ml, limited to maximum one bolus per h. In case of
 persistent pain, orally administered of 5 mg oxycodone every 4-6 hours will be allowed by the
 ward nurses.

 The investigators expect, by administering oxycodone/naloxone in the early postoperative
 period to reduce the length of TEA without impairing the return of the bowel function. This
 could reduce the risk induced by the prolonged TEA (i.e. local infection, malfunction) and
 costs (pain service). This can result in the implementation in the future of a new
 postoperative analgesia concept with the early postoperative administration of an oral pain
 killer, reducing the length of epidural analgesia without impairing the enhanced recovery.

 A total of 90 patients (30 per group) undergoing cystectomy with urinary diversion with
 perioperative thoracic epidural analgesia will be studied.

 Blinding:

 Batches and blinding will be organized by Mundipharma Medical Company (Basel, Switzerland)
 and provided by Mundipharma Research GmbH & Co. KG granting good manufacturing practice
 (GMP). As Targin tablets are oblong in shape and the Oxycontin tablets are round a double
 dummy approach is inevitable to warrant the fully blinding. It will not be able to optically
 recognize the type of drugs administered. The one will contain only placebo, the second 20mg
 of oxycodone (Oxycontin®) and the third a mixture of oxycodone (20mg) and naloxone (10mg)
 (Targin®). Drugs will be orally administered at 12 hours intervals.

 Study nurses on the Department of Urology will bring the randomized blinded drugs to the
 intermediate care unit in a sealed package, only described with only the name of the included
 patient.

 This will allow for blinding of the patient, the patient's nurses of the IMC and ward and
 urologist, and data assessor (including pain service).

 Randomisation will be done by computer generated list, with blocks of 10 patients; allocation
 will be left in concealed opaque and numbered envelopes. Patients will be included strictly
 according to the lowest number.

 Duration of the study:

 The annual case load of cystectomy is around 100 in the investigators' institution per year.
 The investigators expect to recruit the participants within 24 months. To ensure that the
 study can be conducted in the anticipated timeframe, an interim analysis of recruitment is
 scheduled 1 year after Swissmedic study approval. If the recruitment remains below
 expectations and completion of the study in a timely manner is jeopardized, this would result
 in abandoning the Oxycodone arm.

 Sequence of the study:

 Seven days (inclusion the day before surgery, finished after removal of the epidural
 catheter)

 Time course of the study:

 Admission day:

 After informed patient consent, patients will be randomized.

 End of surgery till POD 3, morning:

 The study will start after cystectomy combined with urinary diversion is successfully
 performed in combined anesthesia (general plus TEA). After closure of the abdominal wall,
 continuous epidural analgesia will be maintained with bupivacaine 1.25mg/ml using an
 ambulatory infusion pump. The initial infusion rate will be 8 ml/h, with additional bolus
 volumes of 4 ml (lockout time: 1 h). The infusion rate can be adapted if necessary based on
 assessments made every 4 h to maintain a pain intensity lower than 3 at rest and lower than 5
 during mobilization on the numeric rating scale (NRS), where 0=no pain and 10=worst pain
 imaginable. The maximum infusion rate will be 10 ml/h. This epidural treatment is in
 accordance with the investigators' internal standard and has been successfully implemented in
 the last 15 years. Data on pain intensity, amount of epidural mixture used per 24 h and use
 of rescue analgesics will be recorded daily. In addition, episodes of PONV, first flatus and
 defecation and body weight will be documented.

 POD 3 around 08:00 a.m.:

 According to the randomization, patients will receive blinded batches with 20mg oxycodone,
 20mg oxycodone plus 10mg naloxone or oral placebo every 12 h, starting with 10 mg bid
 respectively 10mg/5mg and move to 20 mg bid (20mg/10mg) the other day. Epidural mixture
 infusion will be reduced in steps of 2 ml according to the NRS score to maintain a pain
 intensity lower than 3 at rest and lower than 5 during mobilization during 6 h. The epidural
 catheter will be removed when during 6 h the rate is 2 ml/h, and the patient has a NRS < 3
 and < 5 at rest and during mobilisation, respectively. If the epidural catheter cannot be
 removed because of the subcutaneous administration of low weighted molecular heparin (LWMH)
 (always around 20:00), the infusion will be stopped (0 ml/h) and the length of stay of the
 epidural catheter registered (length of stay of the epidural catheter= insertion of the
 catheter to rate of epidural mixture =0ml/h), and the catheter will be removed according to
 the investigators' internal guideline (at least 12 h after subcutaneous administration of
 LWMH). The time the epidural infusion was stopped will be recorded as removal of the epidural
 catheter.

 Objective

 The objective of this study is to evaluate the implementation of an oral opioid with or
 without naloxone in the early postoperative period in patients undergoing cystectomy and
 urinary diversion with intraoperative and early postoperative use of TEA. The investigators
 expect an unchanged early return of the bowel function and equal analgesia with a reduced
 length of stay of the epidural catheter (primary endpoint), thus potentially reducing
 epidural catheter associated complications and lowering costs (nursing and pain service).

 Methods

 Trial design:

 Randomized, double blind, parallel groups, single center, intervention placebo controlled
 study

 Setting:

 Single center: Department of Urology, University Hospital Bern, Inselspital.

 Selection of the trial subjects:

 A total of 90 patients (30 per group) undergoing cystectomy with urinary diversion with
 perioperative thoracic epidural analgesia will be studied.

 Phase 4 For clinical trials with drugs: Clinical study phase or phase of clinical development
 (e.g. Phase 1, 2, 3 or 4; or according to ICH E8 para 3.1.3 Human Pharmacology, Therapeutic
 Exploratory, Therapeutic Confirmatory or Therapeutic Use); in case of Medical Device study
 rename and use e.g. "Phase of development".
Inclusion Criteria:

 -  At least 18 years old

 -  Informed Consent as documented by signature

 -  Renal function: eGFR >40ml/min

 -  Normal liver function

 -  Cystectomy with urinary diversion

 -  Use of thoracic epidural analgesia

 Exclusion Criteria

 -  Contraindications to the class of drugs under study, e.g. known hypersensitivity or
 allergy to class of drugs or the investigational product, i.e. known allergy to
 oxycodone naloxone or other excipients

 -  Women who are pregnant or breast feeding, (exclusion for surgery per se)

 -  Known or suspected non-compliance, drug or alcohol abuse

 -  Inability to follow the procedures of the study, e.g. due to language problems,
 psychological disorders, dementia, severe psychiatric disorder, etc. of the
 participant

 -  Severe asthma bronchiale, severe COPD

 -  Severe respiratory depression with hypoxia and/or hypercapnoea, cor pulmonale

 -  Preoperative use of MAO-Inhibitors (or has to be stopped 2 weeks before surgery)

 -  Patients with chronic pain

 -  Patients with regular use of antiemetics, laxatives, opioids or other types of
 analgesics

 -  Preoperative regular use of non steroidal anti inflammatory drugs and steroids