Pethidine - meperidine- and other opioids for pain relief during labor

Pethidine and other opioids

Pethidine (meperidine) is popular for pain relief in labor wards. It is generally safe, though side-effects are not uncommon, some potentially dangerous. Its ability to reduce pain is modest. There are questions regarding the ability of pethidine in labor to increase the risk of drug addiction in newborns during adult life. Novel opioid remifentanil shows some promise in managing labor pain.

After nitrous oxide (the “laughing gas”), pethidine is the most commonly used drug for pain relief in childbirth. It belongs to the group of drugs called opioids. They are derived from opium, a viscous substance that appears on the surface of damaged immature seed pods of the opium poppies, officially called Papaver Somniferum. It contains up to sixteen percent of morphine.

Cultivation of opium poppies for food, anesthesia, and ritual purposes dates back at least to Neolithic Age. Many civilizations – Sumerian, Assyrian, Egyptian, Minoan, Greek, Roman, Persian – each made widespread use of opium, which was the most potent form of pain relief, allowing ancient surgeons to perform serious surgical operations. Opium is mentioned in the most important medical texts of the ancient world, including the writings of Dioscorides, Galen, and Avicenna. First use of opium to relieve pain in labor is found in ancient Chinese writings, thousands of years ago. Widespread medical use of unprocessed opium continued through the American Civil War.

In 1806 Freidrich Wilhelm Adam Serturner (1783-1841), an obscure, uneducated, twenty three year old pharmacist’s assistant with little equipment but loads of curiosity, discovered morphine. Serturner wondered about the medicinal properties of opium, which was widely used by the eighteenth century physicians. In a series of experiments, performed in his spare time and published in 1806, he managed to isolate an organic alkaloid compound from the unprocessed opium. Serturner found that opium with the alkaloid removed had no effect on animals, but the alkaloid itself had ten times the power of processed opium. He named that substance morphine, after Morpheus, the Greek god of dreams, for its tendency to cause sleep. He spent several years experimenting with morphine, often on himself, learning its therapeutic effects as well as its considerable dangers. Although his work was initially ignored, he recognized its significance. “I flatter myself,” he wrote in 1816, that “my observations have explained to a considerable extent the constitution of opium, and that I have enriched chemistry with a new acid (meconic) and with a new alkaline base (morphium), a remarkable substance.” Serturner’s crystallization of morphine was the first isolation of a natural plant alkaloid. It sparked the study of alkaloid chemistry and hastened the emergence of the modern pharmaceutical industry. Morphine was not widely used in clinical practice, however, until the invention of the syringe and hypodermic needle in 1853.

Soon after that morphine was introduced for labor pain relief. It did not become popular because it caused serious side-effects, especially in the babies. Several decades later, in 1902, morphine was re-introduced in labor wards and this time was given in combination with scopolamine, another drug that reduced some side-effects of morphine and allowed to use smaller doses. This combination produced the state of “twilight sleep” which helped the women through labor. This combination still caused significant side-effects but remained popular for many years.

In 1939 pethidine was synthesized and was first used in labor in the early 1940s. From that time onwards, it has become the most commonly used opioid for labor pain relief worldwide. As I already mentioned, in its popularity Pethidine stands second only to the nitrous oxide.

Opioids are potent analgesics and relieve pain well in some conditions and are the first line drugs for treating pain after major surgery. Pethidine has long history of use in obstetric patients and has the reputation of a safe drug. Unfortunately, there are quite a few side-effects, some potentially serious, associated with the use of these drugs, as follows.


Respiratory depression

Opioids suppress breathing. The effect is dose-dependent, in other words the higher the dose of an opioid, the more depressed the breathing gets. In obstetric patients it is especially important because here we deal with two patients, the mother and the baby. All drugs given to the mother get across the placenta and enter the fetus. It is not a problem while the baby is still in the uterus, as it gets all necessary oxygen through the umbilical cord. However, immediately after birth the newborn has to rely on his or hers own breathing, and if large amounts of pethidine are given to the mother the breathing of the neonate may be affected.

Newborns are more sensitive to the effects of opioids, and these drugs also tend to behave differently in their bodies. For example, in the mother’s body the concentration of pethidine is reduced by half after about two and a half hours, while in the newborn it can take as long as twenty hours. Another problem is that pethidine is broken down by the liver into several substances, and one of them, called norpethidine (or normeperidine), can cause subtle depression of the respiration in the newborn that can last for three to five days, even when low doses of pethidine was given to the mother. Babies born from mothers given pethidine generally have lower Apgar scores, though long term consequences have not been documented.

In cases where respiratory depression is serious enough to cause concern the newborn is admitted to the intensive care unit where his breathing is supported by the special machine, the ventilator. This process of artificial breathing by itself has side-effects and complications ranging from insignificant to severe.


Nausea and vomiting

This complication is common in patients receiving general anaesthesia, and there are various ways to at least reduce its ocurrence. Among women in labor it is also quite common. Many causes contribute to nausea and vomiting during labor: pain, anxiety, as well as oxytocin, the drug used for stimulating the activity of the uterus. Opioids also cause nausea and vomiting by stimulating chemoreceptor trigger zone, the area in the brain that is in turn connected with the vomiting center. Pethidine may be potent in producing nausea due to its unique property to increase the levels of serotonin in the brain. Serotonin is the primary substance that regulates the activity of the chemoreceptor trigger zone, and increase in its concentration facilitates nausea and vomiting. Nausea is also more commonly observed in non-smokers and in people prone to motion sickness, becoming nauseous in a car or on airplanes. In addition, the use of nitrous oxide for pain relief in labor has also been suggested as the risk factor for nausea and vomiting. In fact, many patients in labor get these drugs simultaneously.


Pruritis

Pruritis is the itching sensation of the skin. It is common in patients receiving opioids.It varies in intensity and duration, and most of the time is mild. However, small proportion of patients may develop severe pruritis that requires treatment by small doses of naloxone, opioid antagonist. In many places. It is not uncommon to treat opioid induced pruritis with anti-histamine drugs which may cause sleepiness. Another unfortunate problem with pruritis is that once it occurs it is considered a contra-indication to further administration of pethidine, and the choices of pain relief become limited.


Sedation

Opioids cause dose-dependent sedation, and it often goes hand-to-hand with respiratory depression. By itself it is not a problem unless it causes discomfort and interferes with the experience of childbirth. It may affect the quality of pushing during the second stage as well as cause reduced Apgar score in the newborn.


Constipation

Common side-effect that usually occurs after several doses of opioids. Due to intense pushing during the second stage a number of laboring women develop haemorrhoids. In that case constipation may cause considerable discomfort, bleeding and pain during bowel movements in the first several days after delivery.


Less relevant side-effects include developing pinpoint pupils and difficulty in urination. The latter is more common among older men. Occasionally the administration of opioids leads to confusion, severe depression of consciousness, psychosis and hallucinations. There are also concerns of addiction potential of these drugs. However, when they are used for such a short time for the treatment of pain, addiction is extremely rare. Historical record of the use of pethidine in obstetric practice demonstrates its safety, and serious side-effects are.


Despite of popularity of pethidine, its efficacy is modest, as has been demonstrated by several studies. In one such study pethidine was compared with injections of normal saline. 24% of patients in the treatment group reported relief of pain, compared to 7 percent of those who received saline. There was no difference in the intensity of pain between the groups and the incidence of side-effects was higher in pethidine group.

One of the largest surveys on pain relief in childbirth was conducted in the early 1990s in the United Kingdom and is particularly interesting. It was unique in that it assessed pain relief from three points of view: the mother herself, her partner, and the midwife. Of interest was the fact that pethidine was rated much higher as a method of pain relief by the midwife than by the woman or her partner. After labor, forty percent of women – still less than half – said they would choose pethidine for treatment of pain in their next labor.

As mentioned before, addiction of patients to pethidine after being exposed to it in labor is very low. However the situation may be different for newborns. A Swedish study investigated known opioid addicts and their siblings in Stockholm. The data demonstrated that the risk of becoming a drug addict later in life was 4.7 higher for babies whose mothers received drugs three and more times during labor. This trend was also confirmed recently in a study of drug abusing subjects in North America. There is also some data suggesting that receiving drugs during birth may be partially responsible for self-destructive behavior (such as suicide) and amphetamine addiction.

Because of the questionable potency and side-effects of pethidine, other opioids have been tried for relieving pain in labor. Scores of drugs with opioid action were developed over the last several decades, and many alternatives are available. There are drugs with partial opioid action (meptazinol, pentazocine, nalbuphine, butorphanol), weak opioids (tramadol), and, more recently, the potent fast-acting opioids (fentanyl, alfentanyl, sufentanyl and remifentanil). However, the data regarding use of other opioids in labor is limited, and no opioid has convincingly been shown to be superior to pethidine.

New opioid remifentanil shows some promise in managing pain during labor. The effects of this ultra-short opioid last only several minutes and it does not accumulate in the body even when used for a prolonged periods of time. It is very potent and has been used for labor pain with variable success in PCA mode. PCA stands for Patient Controlled Analgesia. With PCA Remifentanil is loaded into the electronic drug dispenser and the control button is given to the patient. Whenever the woman feels that contraction is coming, she presses the button and the machine administers pre-programmed dose of the drug. Preliminary research is promising, and remifentanil may be useful in patients in whom epidural analgesia is contra-indicated. However at this stage the widespread use of this technique has not been recommended. Because of its potency remifentanil also produces potentially serious side-effects, such as respiratory depression and/or fetal bradycardia. The latter often serves as indication of fetal distress requiring caesarean section.

References: 

1. Source: University of Chicago Medical Center. http://opioids.com/morphine/200-anniv.html. 08/07/07

2. Leanne Bricker, Tina Lavender. Parenteral opioids for labor pain relief: A systematic review. J Am Obstet Gynecol 2002;186:S94-109.

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Effectiveness of intravenous meperidine for pain relief in the first stage of labour. J Med Assoc Thai. 2002 Nov;85(11):1169-75.

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8. Jacobson B, Nyberg K, Gronbladh L, Eklund G, Bygdeman M, Rydberg U. Opiate addiction in adult offspring through possible imprinting after obstetric treatment. BMJ 1990;301:1067-70.

9. Nyberg K, Buka SL, Lipsitt LP. Perinatal medication as a potential risk factor for adult drug abuse in a North American cohort. Epidemiology 2000;11:715-6.

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11. Jacobson B, Nyberg K, Eklund G, Bygdeman M, Rydberg U. Obstetric pain medication and eventual adult amphetamine addiction in offspring. Acta Obstet Gynecol Scand 1988;67:677-82.

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Dr. Eugene Smetannikov is a practicing anesthesiologist with the interest in obstetric anesthesia. He is the author of the most comprehensive book on the subject, The Truth About Labor Epidural