Purpose:
Opioid antagonists at ultra-low doses have been used with opioid agonists to prevent or
limit opioid tolerance. Remifentanil, a rapid onset/offset opioid that is often used as
an anesthesia adjunct intraoperatively, has been associated with the development of
hyperalgesia and opioid tolerance postoperatively. Opioid-induced hyperalgesia (OIH)
induced by remifentanil intraoperatively may be a factor contributing to an increase in
postoperative pain as well as difficulty in controlling such pain. The purpose of this
study will be to evaluate whether an ultra-low dose of naloxone, an opioid antagonist,
could block remifentanil-induced hyperalgesia and tolerance following surgery.
This research will help elucidate the degree of OIH after surgeries involving
remifentanil and determine if a new technique can be employed to decrease
remifentanil-induced OIH. By mitigating OIH, patients should have a decrease in
postoperative pain and an increase in patient satisfaction at UCI and other hospitals
where such a technique is employed.
There are 3 study groups: (1) low dose remifentanil (LO, 0.1 micrograms/kg/mL), (2) high
dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL), or (3) high
dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004
micrograms/kg/mL naloxone).
Background:
Opioid-induced hyperalgesia is a paradoxical increase in pain sensitivity following
opioid exposure. The mechanism for this is likely due to an alteration in opioid receptor
signaling with disruption of G-protein coupling and opioid-induced activation and
hypertrophy of spinal glial cells (gliosis). Opioid-induced hyperalgesia has been noted
with many different opioids, and the most well documented hyperalgesic effect is with
remifentanil.
Various agents have been used in an attempt to reduce the development hyperalgesia
following remifentanil. While there are few reports on the effect of ultra-low dose
naloxone on opioid-induced hyperalgesia, recent evidence is emerging regarding its use in
pain management. Ultra-low dose naloxone has been shown to prevent remifentanil-induced
pain hypersensitivities (allodynia and hyperalgesia) in rats. However, there are little
to no studies on reducing the adverse effects of remifentanil with naloxone in human
subjects.
Existing knowledge and previous research:
Attempts have been made with various agents to reduce the development of tolerance and
hyperalgesia following remifentanil. Postoperative hyperalgesia and its prevention has
been studied with ketamine , Magnesium , Gabapentin, Clonidine, Lornoxicam ,
Dextromethorphan , Paracetamol , Morphine , Dexmedetomidine , Adenosine, COX inhibitors ,
Amantadine , Nitrous oxide, Fentanyl, Pregabalin , Buprenorphine, Midazolam,
Dexamethasone. Relevant to our current hypothesis is the report that concomitant
administration of ultra-low dose naloxone and naltrexone with remifentanil prevented OIH.
However, there are no studies on reducing the adverse effects of remifentanil with
ultra-low dose naloxone in human subjects.
While the traditional role of opiate antagonists have been in cases of opioid
overmedication, recent evidence is emerging regarding their use in pain management. Gan
et al. 1997 used an ultra-low dose naloxone infusion (0.00025 mg/kg/h or 0.001 mg/kg/h)
in postoperative patients receiving IV morphine via a patient-controlled analgesia (PCA)
device. Good pain relief was experienced in all groups, however consumption of PCA
morphine was significantly reduced in patients that received the lowest infusion of
naloxone and opioid-induced side effects (nausea, vomiting, pruritus) were reduced by
naloxone at both dose.
Naloxone and/or naltrexone at ultra-low doses may enhance the analgesic effects of
opioids, enhance the antinociceptive effects of methadone, and decrease or block the
development of opioid tolerance in rodents. The combination of oxycodone with an
ultra-low dose of the antagonist naltrexone as a singular oral medication, Oxytrex, has
been developed to prevent the development of tolerance in the treatment of moderate to
severe chronic pain.
Aguado et. al. 2013 recently evaluated the effects of the opioid antagonist, naloxone, on
remifentanil-induced tolerance or hyperalgesia in rats. Hyperalgesia was considered to be
a decrease in mechanical nociceptive thresholds (von Frey), while opioid tolerance was
considered to be a decrease in sevoflurane MAC reduction by remifentanil. An ultra-low
dose of naloxone was able to block remifentanil-induced hyperalgesia and the MAC increase
associated with hyperalgesia, but did not change opioid tolerance under inhaled
anesthesia.