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Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 2 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 6

Prevention of Opioid-Induced Hyperalgesia Following Remifentanil Infusion:  
A Case Report
Lauren Gray, BSN, RN
Affiliation:
Texas Christian University

Funding/Conflict of Interest Disclosure: 
None

KEYWORDS:  Opioid-induced hyperalgesia; postoperative pain; remifentanil; total intravenous anesthesia

Abstract
Remifentanil, a potent mu-opioid agonist, is useful in anesthesia because of its rapid onset and short duration of action. 
However, the same traits that make remifentanil useful can also lead to increased pain sensation when remifentanil 
is discontinued. Nociceptive sensitization following opioids is termed opioid-induced hyperalgesia (OIH). Proposed 
preventive treatments for remifentanil-induced OIH run the spectrum of cost and feasibility. This case report will 
discuss the use of and rationale for readily available techniques aimed at preventing OIH. These techniques include 
intravenous ketamine, inhaled nitrous oxide, oral pregabalin, and gradual cessation of remifentanil infusion.

INTRODUCTION
Increases in postoperative pain occur after intraoperative remifentanil infusions. A 2014 systematic review and meta-analysis 
including 1494 patients found an association between high doses of intraoperative remifentanil and small but significant increases in 
postoperative pain intensity.1 Pain in the postoperative period can lead to activation of the stress response, activation of the sympathetic 
nervous system, and activation of harmful spinal reflex arcs. These processes caused by poorly controlled postoperative pain contribute 
to increased morbidity and mortality resulting from hypercoagulability, immunosuppression, poor wound healing, myocardial ischemia, 
delayed return of gastrointestinal function, and decreased pulmonary function.2 Therefore, if remifentanil is part of the anesthetic 
plan, preventive analgesia becomes an important component of that plan. The purpose of this case report was to evaluate methods for 
preventing opioid-induced hyperalgesia (OIH) after remifentanil infusion.

AEJ



Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 2 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 7

CASE SUMMARY
A 70-year-old, 99-kg, 172-cm man presented with degenerative 
disc disease and was scheduled for a laminectomy with fusion 
from lumbar segment 2 to 5. The patient’s medical history 
included coronary artery disease, hypertension, high cholesterol, 
type 2 diabetes mellitus, neuropathy, obstructive sleep apnea, 
prostate cancer, and low back pain. His surgical history included 
cardiac stenting, prostate removal, bladder stone removal, and 
right shoulder arthroscopy with rotator cuff repair. The patient 
denied having any previous anesthesia complications. His current 
medication treatment included metformin, metoprolol, potassium 
chloride, and nitroglycerine. The patient was noted to have 
medication allergy to levofloxacin (rash, hives). Laboratory results 
and electrocardiography and chest radiography findings were 
unremarkable. No other diagnostic testing was ordered. During 
the preanesthetic assessment, the patient stated he was not having 
current back pain. He described having a history of intermittent 
back pain usually coinciding with activity ranging from 2 to 7 
on a 10-cm visual analogue scale (VAS). Midazolam 2 mg was 
administered intravenously after the standard preprocedural time 
out.
The patient was taken to the operating room. Intraoperative 
monitors included pulse oximetry, electrocardiography, 
noninvasive blood pressure monitoring, carbon dioxide 
capnography, esophageal temperature, bispectral index (Coviden 
Ltd, Dublin, Ireland), and somatosensory evoked potentials. Pre-
induction vital signs were as follows: pulse, 53; blood pressure, 
149/65 mm Hg; oxygen saturation, 97%; respirations, 16; and 
temperature, 36.3°C. Oxygen was administered via face mask at 
10 L/min. After 5 minutes of pre-oxygenation, general anesthesia 
was induced with 100 mg lidocaine, 100 mcg fentanyl, 180 mg 
propofol, and 100 mg succinylcholine intravenously. Direct 
laryngoscopy with a Macintosh #3 blade was performed and 
the airway was secured with a 7.5 endotracheal tube. Correct 
endotracheal tube placement was confirmed with visible chest 
rise, capnography, and auscultation of bilateral breath sounds. 
After induction of anesthesia, the patient was transferred to a 
prone surgical bed. Total intravenous anesthesia was utilized 
because of the need to monitor somatosensory evoked potentials. 
Anesthesia was maintained by using an intravenous infusion of 
100 mcg/kg/min propofol and 0.5 mcg/kg/min remifentanil. 
The propofol infusion was titrated to maintain a bispectral index 
between 40 and 60. The patient showed no physiologic indicators 
of nociception during the procedure, and the remifentanil 
infusion was not titrated. Physiologic indicators of pain were 
considered increases in heart rate or blood pressure above 
baseline. Medical air 1 L/min and oxygen 1 L/min were used 
together for gas flow. Prophylactic antibiotics included 1.5 g 
cefuroxime and 1 g vancomycin administered intravenously.
The propofol infusion was discontinued at the time of surgical 
wound closure. Hydromorphone 0.4 mg was administered 
intravenously. The remifentanil infusion was discontinued. To 
stimulate spontaneous respirations, ventilation settings were 
adjusted to a tidal volume of 450 and a rate of 8 breaths per 
minute to allow PaCO2 to rise. Spontaneous respirations with 
adequate tidal volumes were achieved within 5 minutes. The 
patient was rotated to a supine position. The endotracheal tube 
was removed, and the airway remained patent. The patient was 

transported to the post-anesthesia care unit with oxygen at 8 L/
min via facemask. Postoperative vital signs were as follows: pulse, 
87; blood pressure, 117/71 mm Hg; respiratory rate, 12; SpO2, 
100%; and temperature, 36.2°C. Hydromorphone 1.5 mg was 
administered intravenously at 5-minute intervals in 0.5-mg doses 
in the post-anesthesia care unit. The patient was admitted to the 
hospital for continued evaluation. During a follow-up visit 24 
hours postoperatively, the patient stated that his pain was well 
controlled except for a 30-minute interval when his pain was 7 on 
a 10-cm VAS. This interval of increased pain intensity occurred 3 
hours postoperatively. No other adverse outcomes were noted.
DISCUSSION
The use of remifentanil infusions during general anesthesia has 
been associated with hyperalgesia in the postoperative period. In 
the first systematic review and meta-analysis concerning OIH 
in surgical patients, treatment with high doses of intraoperative 
remifentanil was associated with higher pain intensity during 
the first 24 hours after surgery.1 In the 27 studies included in 
the systematic review, a high dose of remifentanil was typically 
considered an infusion of 0.3 mcg/kg/min. Some of the studies 
used higher or lower doses, but in each study a comparison was 
made between an opioid, predominately remifentanil, and either 
a lower dose of the same opioid or a placebo. The study included 
oropharyngeal, neurosurgical, cardiothoracic, and abdominal 
surgeries. The study acknowledged that a possible cause of the 
increase in pain intensity was an acute opioid tolerance after 
remifentanil infusion, because patients experiencing OIH also 
consumed more morphine in the first 24 hours after surgery.1 
Another possible explanation is that remifentanil causes long-
term potentiation of C-fibers through activation of mu-opioid 
receptors and N-methyl-D-aspartate (NMDA) receptors.3 
Although the exact mechanism is still being determined, 
anesthetic management of patients receiving remifentanil should 
include techniques that will lower the incidence of OIH in the 
postoperative period.
Ketamine infusion
It is postulated that OIH is due to central sensitization through 
activation of NMDA receptors.3 In support of this hypothesis, 
the NMDA receptor antagonist ketamine has been shown to 
decrease postoperative pain intensity and morphine requirements 
in patients receiving remifentanil infusion during general 
anesthesia.4,5 Hong and colleagues used a 0.3-mg/kg intravenous 
bolus of ketamine during induction followed by a 3-mcg/kg/min 
ketamine infusion during surgery to effectively prevent OIH and 
decrease the total amount of opioids required in those undergoing 
general anesthesia utilizing sevoflurane and remifentanil.4 A 
separate study set out to determine the effective dose of ketamine 
to prevent OIH. For a ketamine bolus delivered intravenously 
before skin incision, the ED50 was determined to be 0.24 mg/kg 
and the ED95 was determined to be 0.33 mg/kg.5 If used in this 
case, ketamine could potentially have lessened postoperative pain 
intensity and opioid consumption.
Pregabalin
In 93 patients undergoing general anesthesia for laparoscopic 
urologic surgery where a remifentanil infusion was utilized, 
a single dose of 300 mg pregabalin orally before surgery was 



found to increase the time from the end of surgery to the first 
analgesic requirement, to decrease the amount of pain medication 
via patient-controlled analgesia pump during the first 24 hours 
postoperatively, and to decrease postoperative pain intensity for 
24 hours.6 The study confirmed the existence of OIH by first 
comparing 2 groups who did not receive pregabalin. Patients 
receiving 0.3 mcg/kg/min remifentanil had increased pain 
intensity for 24 hours following surgery compared with patients 
receiving 0.05 mcg/kg/min remifentanil. Furthermore, by adding 
a third group who received the high dose of remifentanil and 
pregabalin, the results of this study showed that a single dose of 
pregabalin could help to prevent OIH resulting from remifentanil 
infusion.6 The pregabalin dose was given 1 hour before anesthesia. 
The likely mechanism is prevention of central pain sensitization 
and increased spinal nerve excitability as opposed to direct 
analgesic activity.6 The patient in this case report did not indicate 
any history of gastroesophageal reflux during the preoperative 
assessment, making this oral drug a viable option for prevention 
of OIH.
Nitrous oxide
The use of nitrous oxide, an NMDA antagonist, has been 
associated with a significant reduction in postoperative OIH 
in those receiving total intravenous anesthesia using propofol 
and remifentanil. The study showed that administering nitrous 
oxide at 70% decreased postoperative OIH for 12 to 18 hours 
when compared with an anesthetic using 100% oxygen.7 It is of 
note that postoperative pain intensity and opioid consumption 
were similar among the 2 groups and that the decrease in OIH 
was measured by using mechanical pain thresholds on the arm.7 
Therefore, nitrous oxide is an option for preventing OIH but may 
be a less potent preventive. Furthermore, in the present case it 
would not have been a viable alternative because total intravenous 
anesthesia was used for ideal neuromonitoring conditions.

Gradual withdrawal of remifentanil infusion
Avoidance of sudden cessation of a remifentanil drip has been 
associated with prevention of OIH.8,9 Rodent studies have 
demonstrated that when an intravenous infusion of 7.5 mcg/
kg/min remifentanil was gradually decreased over 30 minutes, 
the long-term potentiation of C-fibers that accompanies OIH 
was prevented.10 A 2014 study in patients undergoing spinal 
surgery found that abrupt cessation of a remifentanil drip was 
associated with a higher incidence of OIH compared with slow 
cessation over 90 minutes after surgery.9 These results indicate 
that an abbreviated but still pronounced withdrawal beginning at 
the start of surgical wound closure when nociception is typically 
lower could prevent OIH. This method may be effective but not 
practical in fast-paced anesthesia settings. Another alternative in 
longer procedures would be a weaning of a remifentanil infusion 
toward the end of surgery while introducing longer-acting opioids 
to assist in prevention of OIH. This plan would incorporate 
remifentanil dosing guidelines which state that adequate 
postoperative analgesia should be achieved before discontinuation 
of remifentanil infusion.11

SUMMARY
The development of OIH is a concern in patients receiving a 
remifentanil infusion as a component of a general anesthetic.1 
Anesthesia professionals should be aware of this risk. While this 
case report did not involve a patient with excessive hyperalgesia 
postoperatively, there was a 30-minute period during which 
the patient experienced an increased pain intensity. When 
remifentanil infusions are used, it may be prudent to include 
medications that could prevent OIH. Pregabalin 300 mg given 
orally 1 hour before surgery, 0.3 mg/kg ketamine administered as 
an intravenous bolus with or without a 3-mcg/kg/min infusion, 
and 70% inhaled nitrous oxide are viable options for prevention 
of OIH. After the anesthesia professional weighs the risk-benefit 
ratio, these medications may be incorporated. If pharmacologic 
interventions are contraindicated, a gradual withdrawal of the 
remifentanil infusion may aid in the prevention of OIH.

Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 2 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 8



REFERENCES

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11. Dosing. Ultiva (remifentanil HCl) Web site. http://www.ultiva.com/how-to-use-ultiva/dosing. Accessed Feb 22, 2018. 

About the Author
Lauren Gray is completing the final year of a Doctor of Nursing Practice at Texas Christian University. Gray graduated summa cum 
laude from the University of Texas Health Science Center in San Antonio with a Bachelor of Science in Nursing. Before beginning 
her doctoral education, Gray was an intensive care nurse at Methodist Hospital in San Antonio where she actively participated in 
the largest heart failure and heart transplantation program in South Texas. Her current professional interests include pharmacology, 
cardiovascular physiology, regional anesthesia, and infection prevention.

Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 2 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 9


