Introduction

Intravenous opioids have a well-established role in providing analgesia in non-pregnant patients. The obstetric population is different, and clinicians need to have a full understanding of the effects of opioid drugs with regard to both the labouring parturient and the foetus. Labour is well recognised as one of the most painful events a woman may endure and alternatives to the ‘gold standard’ epidural for labour analgesia should be available.

There are four major sub-types of opioid receptors: DOR, MOR, KOR and NOR; all of these are found in the central and peripheral nervous system, with MOR (previously termed mu receptors) also being present in the gastrointestinal tract. Analgesia is predominantly produced by the MOR receptor. Once bound, opioids lead to inhibition of neurotransmitters (norepinephrine, acetylcholine, neuropeptide and substance P) by G-protein-coupled receptor activation . This leads to a reduction in nerve transmission and therefore pain impulses.

The ideal opioid for labour analgesia should have a fast onset of action and duration of effect to cover a contraction (90 s). It should not produce any unwanted side effects for the mother or foetus. Currently, providing systemic analgesia is a challenge as no opioid has yet provided these ideal properties.

Parenteral opioids can be administered by the subcutaneous (SC), intramuscular (IM), intravenous (IV), and epidural or intrathecal route. The intravenous route offers the benefit of a faster onset, which is beneficial for the acute and intermittent pain of labour. However, the IM route has practical benefits of administration without the presence of a physician.

Intravenous opioids can be delivered as either intermittent manual boluses or patient-controlled intravenous analgesia (PCIA). PCIA has superseded intermittent manual boluses as they allow the patient to maintain a degree of control over their pain, providing better satisfaction. The frequent delivery of small doses of opioids leads to a steady state of plasma concentration of drug as opposed to the peaks and troughs seen with intermittent manual boluses. This may lead to a reduction in placental transfer of the drug due to a less favourable concentration gradient across the placenta. Other suggested advantages of a PCIA are less maternal respiratory depression and requirement for anti-emetics and greater overall patient satisfaction . However, as labour progresses, and pain intensity increases, the bolus dose administered may no longer achieve the desired level of analgesia (see Tables 1 and 2 for a summary opioids and dosing regimens).

Meperidine

Meperidine (pethidine) is a synthetic opioid, related to fentanyl and sufentanil. It is more lipid soluble than morphine and crosses the placenta readily. It is metabolised to normeperidine (norpethidine) by the liver. Normeperidine is an active metabolite and a potent respiratory depressant. It has a half-life of 21 h in the mother and up to 63 h in the foetus and can accumulate in both the mother and foetus . This is in comparison with meperidine having a 7 h and 23 h half-life in the mother and foetus, respectively . Normeperidine is pro-convulsant; therefore, meperidine should be avoided in patients at risk of seizures.

Meperidine is most commonly administered intramuscularly (25–50 mg every 4 h). This route has the advantage of being prescribed by midwives in some countries and can be administered up to doses of 100–200 mg IM. However, it has been shown to cause significant sedation, which may be confused with analgesia . Although meperidine effectiveness has been questioned in the literature, a randomised controlled trial comparing IM meperidine with IM saline was prematurely terminated as the meperidine group had a significant reduction in visual analogue scale (VAS) pain scores at 30 min. Although both the sedation scores and the satisfaction scores were high in the meperidine group, the neonatal outcomes were similar in both groups .

Meperidine has been used as an IV agent for labour analgesia. As with most opioids, it has been given as intermittent manual bolus through a PCIA. Meperidine is given intermittently at doses of 25–50 mg IV, with an onset of action of 5–10 min and duration of 2–3 h. Meperidine PCIA usually comprises a bolus dose of 5 mg every 5 min with or without a loading bolus dose of 50 mg.

One study has shown that a bolus dose of 50 mg IV meperidine provides comparable analgesia to 1 g of IV paracetamol . The side effect rate in the meperidine group was 64% compared to 0% in the paracetamol group; this finding casts doubt over its usefulness as an intravenous agent. In a randomised study comparing meperidine, fentanyl and remifentanil PCIA, meperidine was administered at a 5-mg bolus after loading doses of 49.5 mg, lockout 10 min: fentanyl 50 μg loading dose, 20 μg bolus, lockout 5 min and remifentanil 40 μg bolus loading dose, 40 μg bolus, lockout 2 min . At 1 h after initiation of the PCIA, VAS pain scores were reduced in all three groups. At 2 h, the meperidine group scores were similar to baseline, while the fentanyl and remifentanil groups had scores lower than baseline scores. The meperidine group also had the highest rate of conversion to epidural analgesia . Despite the problems outlined, meperidine remains a popular analgesic with almost 85% of UK delivery suites offering IM meperidine to women . This is likely to be due to familiarity, cost and ease of administration.

Meperidine

Meperidine (pethidine) is a synthetic opioid, related to fentanyl and sufentanil. It is more lipid soluble than morphine and crosses the placenta readily. It is metabolised to normeperidine (norpethidine) by the liver. Normeperidine is an active metabolite and a potent respiratory depressant. It has a half-life of 21 h in the mother and up to 63 h in the foetus and can accumulate in both the mother and foetus . This is in comparison with meperidine having a 7 h and 23 h half-life in the mother and foetus, respectively . Normeperidine is pro-convulsant; therefore, meperidine should be avoided in patients at risk of seizures.

Meperidine is most commonly administered intramuscularly (25–50 mg every 4 h). This route has the advantage of being prescribed by midwives in some countries and can be administered up to doses of 100–200 mg IM. However, it has been shown to cause significant sedation, which may be confused with analgesia . Although meperidine effectiveness has been questioned in the literature, a randomised controlled trial comparing IM meperidine with IM saline was prematurely terminated as the meperidine group had a significant reduction in visual analogue scale (VAS) pain scores at 30 min. Although both the sedation scores and the satisfaction scores were high in the meperidine group, the neonatal outcomes were similar in both groups .

Meperidine has been used as an IV agent for labour analgesia. As with most opioids, it has been given as intermittent manual bolus through a PCIA. Meperidine is given intermittently at doses of 25–50 mg IV, with an onset of action of 5–10 min and duration of 2–3 h. Meperidine PCIA usually comprises a bolus dose of 5 mg every 5 min with or without a loading bolus dose of 50 mg.

One study has shown that a bolus dose of 50 mg IV meperidine provides comparable analgesia to 1 g of IV paracetamol . The side effect rate in the meperidine group was 64% compared to 0% in the paracetamol group; this finding casts doubt over its usefulness as an intravenous agent. In a randomised study comparing meperidine, fentanyl and remifentanil PCIA, meperidine was administered at a 5-mg bolus after loading doses of 49.5 mg, lockout 10 min: fentanyl 50 μg loading dose, 20 μg bolus, lockout 5 min and remifentanil 40 μg bolus loading dose, 40 μg bolus, lockout 2 min . At 1 h after initiation of the PCIA, VAS pain scores were reduced in all three groups. At 2 h, the meperidine group scores were similar to baseline, while the fentanyl and remifentanil groups had scores lower than baseline scores. The meperidine group also had the highest rate of conversion to epidural analgesia . Despite the problems outlined, meperidine remains a popular analgesic with almost 85% of UK delivery suites offering IM meperidine to women . This is likely to be due to familiarity, cost and ease of administration.

Morphine

Morphine not only acts primarily on MOR receptors in the central nervous system but also binds with KOR receptors, which mediate spinal analgesia. It is metabolised by the liver to morphine-3-glucuronide (70%) and morphine-6-gluconoride (30%) . Only morphine-6-gluconoride is active, and this compound has an elimination half-life of 120 min, being excreted by the kidneys . The accumulation of morphine-6-gluconoride can cause respiratory depression in the mother; hence, morphine as a PCIA is rarely used for labour with a viable foetus. It is an option for women with intrauterine death, and the sedative effects may be of benefit in this situation. Morphine may cause euphoria, but it has the negative side effect of being a potent emetogenic in high doses.

Diamorphine

Diamorphine (heroin) is a synthetic derivative of morphine. It is a prodrug and metabolised by plasma esterase to several different compounds. One of these is 6-monoacetylmorphine, which is subsequently metabolised to morphine . Diamorphine is used in the UK by the IM route for labour analgesia at doses of 2.5–10 mg, while the IV route can be used at doses of 1–2.5 mg; both doses are given at 4- to 6-h intervals. It is a commonly used analgesic on delivery suites with 34% of respondents of a UK survey reporting to use IM diamorphine routinely .

One study has shown modestly lower pain scores at 60 min with IM diamorphine vs. IM meperidine . However, the average length of labour was 82 min longer in the diamorphine group, leading the authors to conclude that overall, this group had more pain. There was no statistically significant difference in the neonatal outcomes in either group. A study that compared diamorphine PCIA to the IM route showed that PCIA was no more effective in terms of the analgesic effect and in fact had inferior satisfaction scores . As diamorphine may cause marked maternal respiratory depression, and therefore foetal hypoxia, it is rarely used as a PCIA in viable pregnancies.

Fentanyl

Fentanyl is a synthetic opioid which is highly lipid soluble and highly protein bound. It is selective for MOR opioid receptors, 100 times more potent than morphine and 800 times more potent than meperidine . Fentanyl has a fast onset and a short duration of actions (2 min and 30 min, respectively). Fentanyl is metabolised by the liver to compounds that are inactive. These properties have led to it being used for labour analgesia.

Intermittent boluses of 50–100 μg up to once per hour (at maternal request) have been shown to produce short-lived analgesia of 45 min . These doses were also shown to cause brief reductions in foetal heart rate variability (lasting no longer than 30 min). In this study, no difference was observed in Apgar and Neurologic and Adaptive Capacity Scores (NACS) when compared with women who did not receive analgesia . One retrospective study looked at neonatal Apgar scores and naloxone requirement in all mothers who had received a fentanyl PCIA (variable bolus dose, lockout and background infusion rate) over a 2-year period . A high proportion of neonates (14/32) had Apgar scores of ≤6 at 1 min and 3/32 of these required naloxone. At 5 min, the Apgar scores were all ≥7 except for the three neonates who had required naloxone. The low Apgar scores did not correlate with the total dose of fentanyl administered. Fentanyl PCIA is not commonly used in labouring women with a viable foetus. It is offered as an alternative to morphine PCIA, especially if the side effects of nausea and vomiting with morphine are not well tolerated by the mother.

Alfentanil

Alfentanil is a derivative of fentanyl; it is a short acting, highly selective MOR opioid receptor agonist. Because of its short duration of action, its use for labour analgesia is limited to PCIA administration. It is a potent respiratory depressant and is therefore not commonly used during labour.

A randomised trial compared equipotent doses of alfentanil with those of fentanyl PCIA during labour in 23 parturients . There was no difference in VAS pain scores between the groups when the women had <7 cm cervical dilatation. However, the VAS pain scores were higher in the alfentanil group once the parturient had reached 7 cm. On follow-up, after delivery, 42% of mothers in the alfentanil group described their pain relief as inadequate compared to 9% in the fentanyl group .

Sufentanil

Sufentanil is a highly lipophilic and a selective MOR receptor agonist, it is up to 1000 times more potent than morphine . Sufentanil has been compared by the intravenous, epidural and intrathecal route in women in labour. In one study, a single 10 μg dose was given by all three routes. The authors concluded that 10 μg sufentanil provided effective analgesia for up to 2 h when given intrathecally but not when given by the intravenous or epidural routes .

Remifentanil

Initial studies using remifentanil for labour analgesia had high rates of side effects. In one study, all patients withdrew due to inadequate pain relief and unacceptable respiratory depression . A criticism of this study was that rather than PCIA, a third party was administering the bolus, producing a lag between onset of contraction and bolus administration . Subsequent studies showed benefits in its use, and different delivery doses and methods were used to find the optimal regimen.

Doses/optimisation

Dose finding studies showed a large variation in individual requirements for remifentanil to provide adequate labour analgesia . An early feasibility study showed bolus doses of between 0.25 and 0.5 μg/kg reduced pain scores by 30 mm when compared to the baseline , while another reported a median effective bolus dose of 0.4 μg/kg resulted in a median reduction of pain scores by 42 mm .

A range of protocols has been studied with differences in bolus dose, lockout time and the addition of a background infusion. PCIA regimens have ranged from a variable bolus dose of 0.1–1 μg/kg or fixed doses of 20–60 μg, with lock out times between 1 and 4.5 min . Continuous infusion been assessed, and background continuous infusions have been added to a PCIA regimen . The variability in individual requirements may lead to the lack of effective analgesia in fixed dose PCIA regimens.

A study in non-obstetric patients, evaluating the effects of a remifentanil bolus on ventilatory control showed that a 0.5 μg/kg bolus had an onset of effect at 30 s but a peak effect at 2.5 min . As the duration of a uterine contraction is 60–80 s, this may explain the difficulties in timing delivery of a bolus to cover contraction pain. However, it has been suggested that with adequate support and tutoring from staff, women can co-ordinate bolus dose administration and adequate analgesia.

An early study evaluating the addition of a background infusion to a PCIA with bolus doses of 0.25–0.5 mcg/kg did not improve pain scores but led to an increase in the incidence of maternal desaturation and sedation . These results have not been duplicated in other studies, which have suggested the addition of a background infusion between 0.025 and 0.1 μg/kg/min provides more effective analgesia compared to no background infusion .

Lockout times have been studied and vary from 1 min to 3 min. A bolus dose given over 1 min with a lock out of 1 min has also been described. As uterine contractions last from 60 s up to a maximum of 90 s, some argue that a bolus dose will not provide analgesia for that contraction, but will reach its analgesic effect within 1–3 min. The same bolus will have its peak respiratory depressant effect 2–4 min later. From this finding, it has been suggested that the minimum lock out duration should be 3 min to avoid a second dose being administered prior to the peak effect of the previous bolus . A study has evaluated the precise timings when the remifentanil bolus should be given in relation to the contraction to improve efficacy and safety of its use . Remifentanil was given either at the beginning of a contraction or during a contraction pause (aiming for 140 s before the next contraction). No improvement was observed in the analgesic effect of remifentanil when it was delivered during the contraction pause.

The time period over which the bolus is administered may have a role in efficacy of analgesia provided. The literature describes bolus doses being given over different time durations depending on the pump settings, these range from 4 μg s ⁻¹ (40 μg over 10 s) to 0.11 μg s ⁻¹ (40 μg over 3.8 min) . A study evaluated the use of variable bolus dose infusion rates (3 μg s ⁻¹ reducing to 0.12 μg s ⁻¹ ) within a remifentanil PCIA versus conventional bolus rate (1.2 μg s ⁻¹ ); both of these were administered along with a continuous background infusion of 50 μg h ⁻¹ (0.01 μg kg ⁻¹ min ⁻¹ ) . Patients were asked to press the PCIA button at the anticipation of a contraction and hold it until the peak of that contraction; the longer the button was pressed, the larger was the bolus dose of remifentanil given. In the ‘classical’ regimen, the bolus dose was given at a constant infusion rate of 1.2 μg s ⁻¹ (e.g. 25 μg over 22.5 s up to 55 μg over 49.5 s). In the modified regimen, the bolus dose was given at a rate of 3 μg s ⁻¹ for the first 6 s, and the infusion rate was then reduced according to the duration the patient held the button over a 30-s period (e.g. 18 μg over the first 6 s, 14.4 μg over the subsequent 6–12 s and so on). The authors concluded that the duration over which the bolus dose is administered may improve the efficiency of the analgesia provided, as the group that had received the variable infusion rate PCIA had better pain scores and fewer PCIA demands than the conventional group. However, there were significant limitations to this study: the modified regimen not only changed the duration over which the bolus was delivered, but a higher infusion rate and a different infusion profile were also used compared to the conventional regimen; moreover, the sample size was small (23 patients).

A recent evidence-based review of remifentanil for labour analgesia suggested that the initial protocol for a remifentanil PCIA should use a fixed dose of 20–50 μg with a lockout of 1–3 min and no background infusion . It was noted that remifentanil PCIA settings often require adjustment as labour progresses; this may be due to a combination of an increase in pain severity and a decrease in remifentanil efficacy over time. This last point is important when interpreting studies that only quote pain scores over the first 1–2 h of use. The review also suggests the addition of a background infusion may compromise the safety of the remifentanil PCIA, but if required, it should be a low dose of 0.025–0.05 μg kg/min.