Remifentanil during labor
The Dutch experience...


Remifentanil and Labor
by G.M. Woerlee & R. Aronius

© G.M. Woerlee, MBBS, FRCA


Many women regard and undergo labor as the most extreme painful experience in their lives - an experience forced upon them by their sex - genetics means they must undergo such an experience in order to get children. But instead of offering comfort and support, many popular socio-cultural beliefs, and even religions reinforce the worst fears of these women with stories of pain and misery. For example, in the Christian Bible God punishes Eve, the first woman, for disobedience by expelling her and her husband from paradise, telling her:

Unto the woman he said, I will greatly multiply thy sorrow and thy conception; in sorrow thou shalt bring forth children; and thy desire [shall be] to thy husband, and he shall rule over thee. (Bible, Genesis 3:16)

A similar passage is to be found in the Islamic Holy Koran:

And the pains of childbirth drove her to the trunk of a palm tree. She said, "Oh, I wish I had died before this and was in oblivion, forgotten." (Koran 19:23)

Such passages offer only pain and anguish - no comfort. Some people even go so far as to say that “nature” has determined that this be so, because pain has a “valuable function”, or even that “God has willed this be so”. According to such people, women should gratefully accept their genetic lot. But women draw no comfort from such beliefs. Women are the ones undergoing the pains of childbirth. They know such beliefs for what they are - fantasies - and so the pain of childbirth remains to terrify prospective mothers. Luckily not everyone thinks like this, and a variety of techniques have been developed over the years to soften the pangs of childbirth. Several of these techniques are employed in the Rijnland Hospital, (a middle sized general hospital in located in the town of Leiderdorp in the Netherlands).

  • Psychoprophylaxis. Women prepare themselves for childbirth and motherhood by speaking to their mothers, their sisters, their girlfriends, and other women. They read magazines, books, and listen to rumours, stories, and legends. Popular books and magazines provide glowing accounts of happy fulfilling childbirth and wonderful babies. They attend classes to train themselves to relax during their big moment. They learn that labour is not a disease, but a natural process, a part of being alive, and an aspect of being a woman. Many women derive considerable psychological benefit from such antenatal preparations. Even so, not all women and births are the same, and for some women labour pains are unexpectedly worse than they can conceive or endure.
  • Transcutaneous Nerve Stimulation. Electrodes are applied to the back of the women, and electrical pulses stimulate sensory nerves, blocking the pain-gating systems in the spinal cord. But regardless of how wonderful this sounds, this technique is insufficiently effective for many women.
  • Pethidine, with, or without Promethazine. Pethidine has been used for more than 50 years to manage the pain of childbirth. It is used either alone or in combination with the antihistamine, anti-emetic, and weak psychotropic drug Promethazine. However, Pethidine together with, or without Promethazine, is not always effective in alleviating the pain of childbirth.
  • Epidural analgesia. An anaesthesiologist introduces a catheter into the epidural space. Intermittent doses, or a continual infusion of a local anaesthetic drug (with or without added opiate) are administered. Epidural analgesia is a very effective method of managing the pain of childbirth.

Yet while these techniques have advantages, they are sometimes accompanied by disadvantages, and may even be associated with complications. So why treat the “natural pain” of childbirth if treatment is associated with complications?


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Reasons for treating labour pain.

There actually very good reasons for treating labour pain.

  • Exhaustion and pain labour can result in failure of progression of labour.
  • Failure of progression can cause maternal exhaustion and / or foetal distress.
  • Extreme pain, or the personal experience of extreme pain during labour or delivery is related to the occurrence of postnatal depression (Ferber et al 2005, Hiltunen et al 2004).

In conclusion, there are very good reasons for effective management of labour pain, in spite of the fact that some women may feel that the necessity for labour analgesia as a personal failure on their part (Kannan et al 2001). But which form of analgesia? Simply put, both Prthidine and epidural analgesia are very safe forms of labour analgesia that have proven themselves with millions of women over many decades. Even so, what are the disadvantages and complications associated with labour analgesia provided by Pethidine and epidural analgesia?


Disadvantages of Pethidine.

  • Pethidine can cause such a degree of somnolence that some women completely miss the experience of their delivery.
  • Pethidine can induce confusion and even hallucinations.
  • About 30% of women are nauseated and / or vomit.
  • Dizziness is common.
  • The difference between the plasma concentrations of Pethidine needed to induce analgesia and those causing respiratory depression are so small, that the use of Pethidine for management of labour pain is associated with desaturation episodes (SpO2 between 70 to 90%) in about 50% of women (Reed et al 1989, Minnich et al 1990).
  • Elimination of Pethidine from the bodies of both mother and child is relatively slow, which is children newly born from mothers administered Pethidine can be sleepy or suffer from respiratory depression. This latter means that a significant number of babies require specialist resuscitation and drugs to reverse the effects of maternal Pethidine use.


Disadvantages of epidural analgesia.

  • Epidural analgesia is a procedure performed by anesthesiologists, requiring continual specialist anesthesiological backup for safe and efficient utilization.
  • Epidural analgesia forces patients to maintain bed rest in one place.
  • Epidural analgesia is associated with hypotensive episodes.
  • Epidural analgesia increases the likelihood of instrumental delivery by about two to five times (Sharma et al 2004, Liu & Sia 2004).
  • The obstetrician unintentionally exerts more force than otherwise during deliveries performed with the aid of epidural analgesia (Poggi et al 2004).
  • Patients can develop elevated body temperature during epidural analgesia. The cause of this temperature elevation is unknown, but is somehow related to the effect of analgesics on the central nervous system (Gross et al 2002, Yancey et al 2001).
  • Due the efficiency of epidural analgesia, some women feel themselves to be observers than participants in the delivery of their babies, causing them to be dissatisfied with their delivery (Kannan et al 2001).


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Advantages of both systems of analgesia.

Despite all these disadvantages, both Pethidine and epidural analgesia have proven to be both safe and effective for management of labour pain when administered in properly controlled and monitored environments, such as in a modern delivery ward. But how satisfied are parturient women with these forms of analgesia during labour? Various studies show that (Howell et al 2001, Hain et al 2003):

  • 50% to 70% of women are satisfied with intramuscular Pethidine.
  • 90% to 95% are satisfied with epidural analgesia.

The quality of epidural analgesia is evident. But the disadvantages of Pethidine are such that it is questionable whether it still has a place in a modern, technologically advanced obstetrical unit such as exists in most Western European hospitals.


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The promise of Remifentanil.

Remifentanil is a modern mu-receptor active opioid with a very short plasma elimination half life due to rapid metabolism by non-specific tissue esterases present in adults and fetuses. It has the following pharmacokinetic and pharmacodynamic profile:

  • Elimination half life = 9.5 minutes.
  • Context sensitive half life = 3 minutes.
  • Volume of distribution = 0.35 l/kg.
  • Clearance = 2.5 l/kg/hour.
  • t1/2ke0 = 1.3 min.
  • Remifentanil UV:MA raio = 0.88, and the fetal UA:UV ratio = 0.29, clear evidence for extensive fetal metabolism (Kan et al 1998).

These properties indicate that Remifentanil administered either as a constant infusion, or as a PCA (patient controlled analgesia) system, or both would be a very good alternative to Pethidine as an obstetric analgesic, even possessing nearly all the properties of the ideal obstetrical analgesic as defined by Campbell in 2003.


Characteristics of the ideal labor analgesic (Campbell 2003)

  • Maternal and fetal safety
  • Ease of administration
  • Consistent, predictable, rapid onset Maternal composure and control during both the 1st and 2nd stages of labor
  • Analgesia through all stages of labor
  • Devoid of motor blockade, enabling ambulation and various birthing positions
  • Preserve the stimulus for expulsive efforts during the 2nd stage of labor
  • Facilitate the delivery of supplemental analgesia without the need for additional invasive procedures
  • Facilitate the delivery of anesthesia for surgery to avoid the need for general anesthesia


When comparing this list with the kinetic and dynamic parameters, Remifentanil does indeed seem to satisfy all requirements. But has this promise been confirmed by investigation?


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Comparison of Remifentanil with other analgesic techniques.

pharmacokinetic bookComparison of the efficiency of Remifentanil PCA with the analgesia delivered by intramuscular Pethidine clearly demonstrates that the quality of analgesia is superior to that of Pethidine, but without any neonatal respiratory depression, while the number and depth of desaturation episodes (SpO2 < 94%) was comparable to that of Pethidine (Blair et al 2005, Evron et al 2005, Thurlow et al 2005, Volikas & Male 2001).

Remifentanil PCA has been compared to epidural analgesia with a mixture of levobupivacaine/Fentanyl. Both systems of analgesia caused a similar incidence of clinically insignificant desaturation episodes, and no neonatal respiratory depression, although the epidural analgesia was superior to that of Remifentanil PCA (Volmanen et al 2005).

All this indicates that Remifentanil PCA / infusion analgesia has the potential to provide an analgesic satisfaction for women with labor pain less than that due to epidural analgesia, but better than that due to intramuscular Pethidine. Yet, in spite of this promising profile, Remifentanil analgesia is not yet a routine technique in obstetrical units. The main reasons for this are the variable experiences reported by some researchers using a variety of administration techniques. These differences are readily explained with basic physiology, pharmacokinetics, and pharmacodynamics such as explained in Chapter 11 in the book Gerry's Real World Guide to Pharmacokinetics & Other Things.


Remifentanil PCA bolus only

Some studies have reported very variable, or even negative experiences with PCA Remifentanil administered for labor pain (Blair et al 2001, Volmanen et al 2002, Olufolabi et al 2001), while others have reported extremely satisfactory and safe analgesia (Blair et al 2005, Evron et al 2005, Thurlow et al 2002, Volikas & Male 2001, Volikas et al 2005, Volmanen et al 2005). What are the reasons for the sometimes negative experiences, or experiences that Remifentanil is ineffective?

  • Incautious manual administration techniques causing serious hypoxia, such as in the report of Olufolabi et al 2000, or simple overdosage with an electronic PCA pump. According to the dosage guidelines for use of Remifentanil Ultiva warnings website 2005), thoracic rigidity associated with respiratory depression in spontaneously breathing adults occurs after an i.v. bolus of >1 mcg/kg administered over 30-60 seconds, or an infusion at a rate greater than 0.1 mcg/kg/min. Furthermore, this site warns that respiratory depression may also occur with lower bolus dosages if a concurrent i.v. infusion of Remifentanil is administered.
  • Remifentanil PCA is administered with an electronic pump attached to an i.v. infusion. During a contraction, the venous pressure increases, as a result of which the intravenous infusion no longer functions, and can even reverse. The i.v. canula is inefficiently placed as a result of which little of the PCA Remifentanil enters the patient when desired. The end result of either is an inefficient PCA technique.
  • A contraction lasts about 60-90 seconds. Now if a woman presses the PCA button at the beginning of an infusion, it will take 20-30 seconds before any of the administered PCA bolus begins to arrive in her brain (one arm-brain circulation time). Remifentanil t1/2ke0 = 1.3 minutes. So it will take about two minutes before the PCA bolus really begins to be effective, a time when the contraction very likely has passed. Furthermore the context sensitive half-life of Remifentanil is about 3 minutes, meaning that significant amounts of Remifentanil will be eliminated from the plasma between contractions. This indicates that incorrect PCA timing protocols may also be the cause of the variable results achieved by some studies with Remifentanil PCA.


Physiology explains why intermittent bolus doses give erratic results

The figure below demonstrates clearly how the simple physiology of circulation times, the t1/2ke0, and the speed of administration explains why intermittent bolus doses of Remifentanil administered at the start of a contraction fails to provide any analgesia analgesia.



This diagram shows quite clearly that the most succesful Remifentanil regimen is a combination of a continuous background infusion of Remifentanil, combined with intermittent rescue doses of Remifentanil. Indeed, the efficacy of such a regimen is demonstrated by both clinical experience and some studies.


Continuous infusion plus PCA bolus administration

More consistent results have been reported from studies using a constant i.v. infusion at rates between 0.025-0.05 mcg/kg/min combined with rescue PCA bolus doses of 0.25-0.5 mcg/kg. These studies report good analgesia, no neonatal respiratory depression, and an incidence and severity of desaturation incidents equivalent to Pethidine (Blair et al 2005, Roelants et al 2001).


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Hypoxia due to Remifentanil

Many people express fear that the use of Remifentanil PCA / infusion technique during labor will be associated with hypoxia. So it is worthwhile examining this point. I will begin with the question of whether hypoxic episodes occur during labor in women receiving no analgesia, or the current standard labor analgesic techniques.

Examination of the literature reveals that hypoxic, or desaturation episodes occur quite frequently during normal labor. One study even revealed that women who received absolutely no analgesia had more hypoxic episodes (SpO2 < 94%) in the second stage of labor than women who received analgesia (Griffin & Reynolds 1995, see also Porter et al 1992). Other older studies revealed that as many as 50% of women had desaturation events varying between SpO2 of 90% to as low as 70%, apparently unrelated to opiate use (Reed 1989, Minnich 1990, Deckardt et al 1987). There are several possible reasons for this.

  • Hypoxia due to nitrous oxide - hypoxic mixtures and diffusion hypoxia.
  • Respiratory depression due to Pethidine.
  • Post-hyperventilation apnea.
  • Pushing for long periods during contractions.
  • Combinations of these factors.

In other words, hypoxia is quite common during normal delivery, and especially when high doses of Pethidine, with or without nitrous oxide are used. All well performed Remifentanil studies show that provided the dosages, and the administration speeds of these dosages remain within the guidelines specified on the Remifentanil warning website dated September 2005, that the incidence of hypoxic episodes is no greater than that due to Pethidine alone (Blair et al 2005, Evron et al 2005, Thurlow et al 2002, Volikas & Male 2001, Volikas et al 2005, Volmanen et al 2005). The conclusion is that hypoxic moments occur relatively often during labor, but that hypoxic incidents due to Remifentanil use within the guidelines is not associated with any more hypoxia than Pethidine, a drug in use for more than 50 years. Furthermore, Remifentanil is a more effective analgesic than Pethidine, and is associated with no long lasting neonatal and maternal sedation or somnolence, or neonatal respiratory depression. The conclusion is evident - Remifentanil PCA / infusion (Remifentanil PCIA) is a good replacement for Pethidine in modern Western obstetrical units.


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Requirements for safe use of Remifentanil PCIA

What are the conditions required for safe Remifentanil analgesia during labor? All successful introductions of a Remifentanil analgesia system for patients in labor must satisfy a number of conditions for safety and efficiency related to organization and the technical requirements of the apparatus used.

  • Remifentanil PCIA for labor analgesia is not a system that can be applied in an environment where no-one has experience or training. Just as with epidural analgesia, Remifentanil PCIA is VERY unsafe when employed occasionally in an environment where no-one has experience or training it its employment.
  • An absolute precondition is a will to introduce such a system in the hospital. If this will is not present - safe introduction doomed to failure.
  • Anesthesiologists and obstetricians MUST work together to develop a trajectory for introduction of this system. The system employed in the Rijnland Hospital, as in other hospitals, is one where one anesthesiologist together with one obstetrician tested the system during a period that both were present in the hospital. During this trial period, the responsible anesthesiologist and obstetrician are primarily responsible for patient selection, application, backup, and instruction in the use of this technique. Other hospitals in the Netherlands have employed this same system with success. The use of Remifentanil PCIA can be expanded after the obstetrical unit and physicians have experience with this system.
  • Remifentanil PCIA is a system where more apparatus is employed than with other systems of obstetrical analgesia. Disasters due to ignorance and inexperience will occur if anyone or everyone is allowed to employ this system, and administer doses of Remifentanil as wished. Accordingly, only a small group of people within an obstetrical unit should be permitted to apply this system to women in labor. This can be done with a small group of dedicated residents or experienced midwives whose presence is rostered 24/7.
  • A syringe pump with PCIA capability, i.e. a programmable electronic syringe pump able to deliver a constant infusion of a drug (I), at the same time as patient controlled analgesia (PCA). The best and safest syringe pumps are programmable electronic syringe pumps with lockable administration regimens, so that no-one is able to inadvertently change the settings. This prevents inadvertent misunderstanding and faults, as well as preventing puposeful changes of administration rates.
  • A correctly positioned i.v. infusion with a correctly placed one-way valve is absolutely essential for safety and success (see photo of a setup below). Why a one-way valve? An electronic syringe pump is required to administer the drug at a fixed rate, but a number of problems can occur when the drug arrives in the intravenous line. Venous pressure rises due to labor pains, pushing, valsalva maneuvers, delivery, etc. Furthermore the drip needle may be placed such that it is kinked, resulting in irregular delivery of IV fluids, and backflow of Remifentanil solution in the IV tubing. The result of both effects is that Remifentanil flows back up the IV tubing, and when the IV works normally again, the woman receives a larger than intended bolus dose of Remifentanil with all attendant consequences. See photograph for one setup of the one-way valve (numbers: 1 - intravenous infusion line; 2 - one-way valve; 3 - line for oxytocin or other drugs; 4 - line to Remifentanil PCIA pump).
  • Our protcol includes a separate sub-protocol for replacing an empty Remifentanil syringe with a full syringe. The reason is that when the empty syringe is replaced with a new full syringe, an extra Remifentanil bolus of unknown size may be inadvertently administered when positioning the new syringe in the syringe pump. This inadvertent Remifentanil bolus may have significant effects. A separate syringe-change sub-protocol avoids this problem.
  • In the Rijnland Hospital we have arranged with the hospital pharmacist that the hospital only stocks one size of Remifentanil ampules. In our hospital we only have 2 mg Remifentanil ampules. This prevents inadvertent mixing of incorrect Remifentanil concentrations.
  • We use a background i.v. Remifentanil infusion rate of about 0.025 mcg/kg/min, which is a level well below an infusion rate causing respiratory depression. Studies also show that a constant background infusion rate is associated with less respiratory depression. Translated into practical terms this means that the i.v. Remifentanil infusion rate varies between 80-120 mcg/hr. We consider 120 mcg/hr to be a maximum infusion rate when combined with a person who administers a maximum bolus rate. To keep matters simple, we use just three fixed background infusion rates which can be selected from the menu of the infusion pump. These rates are: 80, 100, 120 mcg/hr.
  • We use a PCA rescue dose of between 0.25-0.5 mcg/kg. In practical terms we fix the Remifentanil bolus dose at 30 mcg for all body weights. This PCA bolus dose is administered over one minute to minimize the chance of respiratory depression. The subsequent lock-out time is five minutes. This lock-out time is longer than many studies describe, but we choose to err on the side of safety. If the patient tries to obtain the maximum amount of PCA bolus doses at a maximum infusion rate, the maximum rate of Remifentanil administration for an 80 kg adult is then about 0.08 mcg/kg/min, a rate within the maximum advised safe infusion rate (Ultiva warning site 2005).
  • The following maternal parameters should be monitored and registered: SpO2, respiratory rate, pulse rate, blood pressure. And in the newborn children: APGAR scores, as well as scalp pH.
remifentanil iv setup


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But Remifentanil is not registered for use during labor!

Remifentanil is not registered for use during labor. However, Remifentanil is registered for use in humans, albeit in another setting. This means that Remifentanil can be used in humans, but that the use of Remifentanil for labor analgesia is "off-label" use of Remifentanil. "Off-label" use of drugs is permissible, and even very common, but is associated with a number of conditions. These are:

  • Tell the patient that this is "off-label" use.
  • There is no really good alternative therapy.
  • There is solid research confirming the efficacy of the use of this drug for this particular "off-label" use.
  • Good monitoring of the patient.

There are several good reviews of the legal basis for "off-label" use of drugs. These regulations are similar in most countries. A good review of "off-label" use in The Netherlands is that by Lisman 2004, a good article for of "off-label" use in Australia is that by Gazarian 2006, in the USA by Murphy 1998, and in the UK by Nunn 2002.


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Published experience of Remifentanil for labor pain

After our initial successful trial of Remifentanil PCIA during 2005, we started offering Remifentanil PCIA as a standard obstetric analgesic technique in the Rijnland Hospital from December 2005. Since December 2005, more than 25 hospitals in the Netherlands have introduced Remifentanil PCIA as a standard analgesic technique together with epidural analgesia and Pethidine.

But what are the experiences with Remifentanil PCIA, and how safe is Remifentanil used for labor pain? Several studies reveal that REmifentanilk PCIA is a valuable extra analgesic technique for managing labor pain.

Harbers et al who work in the TweeSteden Hospital in Tilburg, The Netherlands, have described their experiences with 305 patients administered Remifentanil PCIA for labor pain. They employed a protocol almost identical to that described on this website (Habers 2008).


Experiences with 305 patients
using Remifentanil PCIA for labor (Habers 2008)

SpO2 continually < 93% - 22 patients (7,2%)
Hypotension - 9 patients (3%)
Spontaneous delivery - 70%
Vacuum extraction - 16%
Cesarean section - 14%
Apgar scores - two children with Apgar < 7 after 5 minutes


Dr. T. vd Zwan and his colleagues in the Haga Ziekenhuis, The Hague, The Netherlands, have analyzed their experiences with obstetrical periods during two yeas. In one year they analyzed the pattern of analgesic use without Remifentanil PCIA, and in the second year, after introduction of Remifentanil PCIA. Their experiences were presented at the annual meeting of the Netherlands Society of Anesthesiology in 2008. They found that Remifentanil PCIA was more effective than Pethidine, but less effective than Epidural analgesia. The result was that the use of epidural analgesia and Pethidine decreased (Zwan 2008).


remifentanil versus pethidine and remifentanil and epidural
None = no analgesia; Various = various forms of analgesia, usually Pethidine; Epidural = epidural analgesia


Experiences with 248 patients
using Remifentanil PCIA for labor pain (Zwan 2008)

SpO2 continually < 91% - 2 patients (1%)
Spontaneous delivery - 62,1%
Vacuum extraction - 21,7%
Cesarean section - 16,5%


Remifentanil PCIA has been used as a standard analgesic technique since September 2005 in the Ulster Hospital, Belfast, Ireland. Dr. N. Gupta and his colleagues have analyzed their experiences with 5410 patients who delivered in this hospital during slightly more than two years (Gupta 2008).


Experiences with 1508 patients
using Remifentanil PCIA for labor pain (Gupta 2008)

Type of analgesia
Remifentanil PCIA - 1508 patients (28%)
(N.B. conversion Remifentanil to epidural 10%)
Epidural analgesia - 1200 patients (22%)


Frequency cesarean section vs analgesia technique
Epidural analgesia - 22%
Remifentanil PCIA - 13%
Pethidine - 13,5%


Frequency vacuum extraction vs analgesia technique
Epidural analgesia - 48%
Remifentanil PCIA - 31%
Pethidine - 41%


Apgar scores
Comparable for all analgesic techniques


The conclusion able to be drawn from these experiences is clear - PROVIDED Remifentanil PCIA is used carefully according to a strict protocol, it is a valuable extra technique for providing analgesia for women in labor.


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Those interested in reading an extensive protocol Remifentanil PCA / infusion during labour, as used in the Rijnland Hospital, can click on the navigation bar above.


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