Pilot study: postoperative pain reduction by pre emptive N-Acetylcysteine

Currently approximately 240 million surgical procedures are done worldwide on a
yearly basis. Inguinal hernia repair is one of the most performed surgeries in
ambulatory setting. Despite currently available analgesic drugs, post surgical
pain management remains challenging in this group of patients, as the pain
score appears inadequate (mean VAS of 5.8 +/- 1.22 cm) one day after surgery
with the use of common analgesics. Beside accounting for patient discomfort,
pain is also a major contributor to prolonged length of hospital stay and is a
health care quality indicator.
With multimodal pain management the intention is to reduce pain with less side
effects of analgesics. Multimodal pain management is the combination of
different pharmacologic mechanisms of action, which work by acting at different
sites within the central and peripheral nervous system, thereby having an
additive or synergistic effect and reducing the necessity of opiates.
With this in mind, a potential new target for analgesic drugs are group- II
metabotropic glutamate receptors subtypes (mGlu2 and mGlu3 receptors) localized
in the spinal cord and other regions of the nociceptive system. Growing
evidence from animal models show that activation of these receptors occur via
the glutamate:cystein antiporter and can induce analgesia in models of
inflammatory and neuropathic pain. They depress pain transmission at synapses
between primary afferent fibers and second order sensory neurons on the dorsal
horn of the spinal cord.
N-Acetylcysteine (NAC) is on the market since 1968 and is an over the counter
available agent, mostly known for its role as mucolytic agent in cystic
fibrosis and for the treatment of acetaminophen intoxication. It is a safe
agent with little to no side effects. Recent studies have shown NAC can inhibit
nociceptive transmission in rats and in healthy humans.NAC can induce analgesia
by activating the glutamate:cystein antiporter, causing endogenous activation
of the mGlu2/3 receptors.
Therefore, NAC can potentially become a cheap and safe additive in the
multimodal pain management. However, evidence for usage of NAC in the context
of multimodal pain management is still lacking. Only one available study in
humans evaluated the effect of NAC in the perioperative setting. Despite being
a randomised controlled trial, there are several limitations in this study;
the study arms are too small and only morphine consumption is presented. Also,
blinding might have not as good as suggested since oral NAC has a typical
flavour and the placebo was lemonade. Due to these limitations, still no answer
on the question whether NAC can be an additive in current multimodal
painmanagement is provided.

Primary Objective:
To evaluate the efficacy of intravenous NAC in comparison with placebo in terms
of pain relief after unilateral inguinal hernia repair measured by a visual
analogue scale (VAS 0-100) at day 1 after surgery.

Secondary Objective(s):
1. Difference in pain scores between NAC and placebo direct after surgery,
before discharge and in following 3 days postoperative.
2. Difference in time before first pain medication is administered
postoperative between NAC and placebo.
3. Difference in total consumption of opiates in the hospital (mg) between NAC
and placebo.
4. Difference in time from surgery to discharge between NAC and placebo.
5. Difference in postoperative pain medication at home necessary to reach
adequate pain relief between NAC and placebo ( Acetaminophen /NSAID*s/opiates).
6. If there is a difference in 5, is there also a difference in adverse effects
of pain medication (like nausea, obstipation) between NAC and placebo.

The study will be a single centre double blinded randomized placebo controlled
trial

The following NAC infusion regimen will be conducted. One hour prior to
surgery, the patients will receive 150 mg/kg in 200 ml intravenous bolus over
15 minutes. During NAC infusion, patients vital signs will be adequately
monitored.

Patients who are not included in the treatment arm of the study will receive
intravenous saline instead with identical look of NAC in the same timeframe and
dosage (200ml).

Patients will need to be admitted earlier in the hospital prior to surgery, to
make sure they receive study medication in time.
An intravenous line will be placed on the ward to be able to administer study
medication, however, this same line can be used during and after surgery.
During administration of the study medication subjects will be monitored
respiratory and hemodynamically, to ensure possible side effects of NAC are
captured.
Oral NAC is safe agent and even over the counter available in the Netherlands.
Subjects will have little extra risks due to the intravenous NAC given in this
concentration. The main risk is the occurrence an anaphylactoid reaction, which
is easily treated by antihistaminic and seldom described as serious in the
literature. [1-5] Careful monitoring of subjects will ensure any potential side
effect or adverse event are noticed and treated as quickly as possible.
After discharge patient receive a diary and will record: 1) VAS at
predetermined time, 2) pain medication used, 3) side effects of pain medication
(nausea, obstipation, dizziness) and 4) overall satisfaction.
Total time investment of participants should not exceed more than 2 hours in
total.