What is Pethidine?
Pethidine, more widely known in the United States as meperidine (brand name Demerol), is a synthetic opioid analgesic belonging to the phenylpiperidine class of drugs. It was first developed in Germany in the late 1930s and was once a widely used opioid for managing a variety of pain conditions. However, due to its significant side effect profile and the development of more favorable alternatives, its use has declined over the years. Pethidine is classified as a Schedule II controlled substance due to its high potential for abuse and dependence.
How Pethidine Works: Mechanism of Action
Like other opioid analgesics, pethidine's primary action is in the central nervous system (CNS), where it binds to and activates mu-opioid receptors. This activation produces a range of effects, including analgesia (pain relief), sedation, and euphoria.
In addition to its mu-opioid receptor activity, pethidine also has other pharmacological actions that distinguish it from other opioids. These include:
- Kappa-opioid receptor stimulation: This contributes to its anti-shivering effect, making it useful in certain perioperative settings to treat postanesthetic shivering.
- Anticholinergic properties: Unlike morphine, pethidine has atropine-like properties that can lead to side effects such as a dry mouth and blurred vision. This property also means it does not cause pupillary constriction (miosis) and was once incorrectly believed to be superior for managing biliary and renal colic pain.
- Local anesthetic effects: Pethidine possesses some local anesthetic properties due to its interaction with sodium ion channels.
- Neurotransmitter reuptake inhibition: It inhibits the reuptake of dopamine and norepinephrine, which contributes to some of its stimulant effects.
Medical Uses
Pethidine is indicated for short-term treatment of moderate to severe pain when other treatments are inadequate. Its rapid onset and short duration of action make it suitable for specific situations, but it is not recommended for chronic pain management due to its toxic metabolite.
Some of its approved uses include:
- Acute pain relief: Used for moderate to severe, acute pain that requires an opioid, especially when other pain medications are not effective or tolerated.
- Obstetric analgesia: Commonly used in labor and delivery for pain relief, though its potential effects on the newborn are a concern.
- Preoperative medication: Administered before surgery to help with pain and reduce anxiety.
- Postanesthetic shivering: An effective option for managing shivering after anesthesia, possibly related to its effect on kappa-opioid receptors.
Side Effects and Risks
Pethidine carries several side effects and serious risks, many of which are related to its primary metabolite, normeperidine. Normeperidine has a much longer half-life than pethidine and accumulates in the body, particularly in patients with impaired kidney function, leading to neurotoxicity.
Common side effects
- Nausea and vomiting
- Dizziness and lightheadedness
- Drowsiness
- Constipation
- Dry mouth
- Sweating
Serious adverse effects
- Respiratory depression: Life-threatening breathing problems can occur, especially with high doses or in patients with existing respiratory issues.
- CNS toxicity: Accumulation of normeperidine can cause agitation, tremors, restlessness, and seizures. This is a major reason why pethidine is not recommended for long-term use.
- Serotonin syndrome: A potentially fatal drug interaction can occur if pethidine is used concurrently with other serotonergic medications, such as MAOIs and SSRIs. This interaction was implicated in the death of Libby Zion, which led to significant changes in medical residency regulations.
- Addiction and dependence: Like other opioids, pethidine has a high potential for abuse and dependence, which may develop even with therapeutic use.
Pethidine vs. Morphine: A Comparison
| Feature | Pethidine (Meperidine) | Morphine |
|---|---|---|
| Mechanism of Action | Primarily a mu-opioid receptor agonist, but also has anticholinergic, local anesthetic, and dopamine/norepinephrine reuptake inhibition effects. | Primarily a mu-opioid receptor agonist. |
| Potency | Less potent than morphine. | The standard against which other opioid potencies are measured. |
| Duration of Action | Relatively short-acting (2-4 hours). | Longer-acting than pethidine (3-4 hours). |
| Active Metabolite | Normeperidine: Has a long half-life and is neurotoxic, causing seizures and CNS toxicity with accumulation, especially in renal failure. | Morphine-6-glucuronide (M6G): A potent analgesic metabolite, but less neurotoxic than normeperidine. |
| Side Effects | Similar to other opioids but with an increased risk of CNS toxicity (seizures, agitation) due to normeperidine accumulation, and serotonin syndrome due to interactions with serotonergic drugs. | Standard opioid side effects (respiratory depression, constipation, sedation). |
| Current Medical Use | Use has decreased significantly due to risks; mostly reserved for specific applications like postanesthetic shivering. | Remains a standard for managing severe pain. |
Pethidine and Pregnancy
Pethidine readily crosses the placenta and is often used for pain relief during labor. However, this carries certain risks for the newborn, especially if delivery occurs within 2 to 4 hours of administration.
- Neonatal respiratory depression: The baby may experience respiratory depression at birth, an effect that can be reversed with naloxone.
- Neonatal withdrawal syndrome: Regular use during pregnancy can lead to drug dependence in the fetus, causing withdrawal symptoms after birth, including irritability and sleep disturbances.
- Prolonged effects: The immaturity of the newborn's liver and kidneys means that pethidine and its metabolite, normeperidine, are eliminated very slowly, potentially causing symptoms to persist for several days.
Pethidine Withdrawal
Like other opioid analgesics, abrupt cessation of pethidine, especially after prolonged use, can lead to withdrawal symptoms. The severity can vary, but generally includes physical and psychological effects.
Early withdrawal symptoms may include:
- Anxiety and agitation
- Muscle aches
- Increased tearing and runny nose
- Sweating and yawning
- Insomnia
Late withdrawal symptoms may include:
- Abdominal cramping
- Nausea and vomiting
- Diarrhea
- Dilated pupils
- Rapid heart rate and high blood pressure
Contraindications and Safety Precautions
Several conditions contraindicate the use of pethidine to avoid potentially serious and even fatal outcomes.
- MAO Inhibitors: Pethidine should never be used in patients who have taken MAO inhibitors within the last 14 days, as it can cause fatal serotonin syndrome.
- Respiratory conditions: It is contraindicated in patients with severe respiratory depression, asthma, or chronic obstructive pulmonary disease (COPD).
- Renal and Hepatic Impairment: Patients with liver or kidney disease are at a higher risk of normeperidine accumulation and related CNS toxicity.
- Head injuries: Pethidine can raise intracranial pressure, making it dangerous for patients with head injuries or brain tumors.
- Dependence and Addiction: A history of substance abuse or a diagnosed mental health disorder increases the risk of misuse and dependence.
For more detailed information on precautions and safety, refer to the MedlinePlus Drug Information page on meperidine.
Conclusion
While pethidine was once a popular opioid for pain relief, its use has significantly decreased over time due to the major risks associated with its neurotoxic metabolite, normeperidine. Safer and more effective opioid and non-opioid alternatives are now available for managing most types of pain. The risk of seizures, especially with chronic use or in patients with kidney problems, and potentially fatal interactions with other medications like MAOIs, have largely relegated pethidine to a less prominent role in modern pain management. Despite this, it retains a limited but valuable use for specific indications, such as treating postanesthetic shivering.
