Dolantin (Pethidine)
Reserve opioid, prescribed cautiously today
Dolantin is the well known brand name of pethidine, a synthetic opioid from the 1930s still marketed in Germany by Sanofi as an injection and tablet form. Generics are also available. For decades pethidine was a widely used analgesic in obstetrics, anaesthesia and postoperative pain therapy. With growing knowledge about the specific risks of the substance and the availability of better alternatives such as piritramide, morphine or fentanyl, its use has declined markedly.
The particular problems of pethidine are the active toxic metabolite norpethidine, a relatively short duration of action, a serotonergic component with risk of serotonin syndrome and a pro convulsant effect. WHO and most current guidelines advise against routine use and recommend the substance only in very specific situations. Pethidine is a controlled substance under the German Narcotics Act.
Mechanism of Action
Pethidine is a full agonist at the μ opioid receptor and also binds to κ and δ receptors. Analgesic potency is roughly one tenth that of morphine; parenterally a 100 mg dose corresponds to about 10 to 15 mg morphine. The substance has pronounced lipophilicity, which accounts for the rapid onset of action in 15 to 30 minutes.
Unlike morphine, pethidine has a mild anticholinergic effect (tachycardia rather than bradycardia, dry mouth, voiding problems) and inhibits central serotonin reuptake. From this second property comes the risk of serotonin syndrome, especially when combined with MAO inhibitors, SSRIs, SNRIs, tramadol or linezolid.
Metabolism occurs mainly in the liver to norpethidine, a metabolite with a half life of 14 to 21 hours. Norpethidine is analgesically weaker but neurotoxic. It lowers the seizure threshold and can trigger myoclonus, tremor, agitation and seizures. Particularly at risk are patients with renal impairment, older people and patients on long term therapy. Pethidine is therefore unsuitable for chronic pain therapy.
Indications
- Postoperative acute pain as a single dose in special situations, no longer a routine option
- Labour analgesia parenterally; because of neonatal respiratory depression and poor analgesic efficacy, modern guidelines increasingly favour epidural analgesia or remifentanil PCA
- Severe postoperative shivering at low dose of 25 mg intravenously, a classic and still accepted indication
- Analgesia in pancreatitis and biliary colic, historically preferred; current guidelines favour piritramide or morphine
- Adjunct in anaesthesia induction, today largely replaced by more modern opioids
Dosage and Administration
Adults, parenteral: 25 to 100 mg intramuscular, subcutaneous or slow intravenous every 3 to 4 hours. Oral: 50 to 100 mg every 3 to 4 hours. Total daily dose should not exceed 500 mg parenterally or orally. Keep treatment as short as possible, ideally limited to single doses.
Post anaesthesia shivering: 12.5 to 25 mg intravenously as a single dose, usually promptly effective. Children: from the age of 1 year 0.5 to 1 mg per kg, used cautiously and only in experienced hands; prefer modern alternatives.
Renal impairment: because of norpethidine accumulation, dose reduction or switch to another opioid is advised; in severe impairment pethidine is contraindicated. Hepatic impairment: dose reduction is required because of slower breakdown. Intravenous use only under continuous monitoring of circulation and breathing, with naloxone at hand.
Side Effects
Very common and common: nausea, vomiting, constipation, sedation, respiratory depression (dose dependent), dizziness, headache, tachycardia, dry mouth, voiding problems, histamine release with pruritus.
Uncommon: hypotension (especially after rapid intravenous dosing), bronchospasm, confusion, hallucinations, miosis.
Specific: norpethidine intoxication with myoclonus, tremor, agitation and seizures under high or prolonged dosing. Serotonin syndrome in combination with serotonergic substances. Tolerance, physical dependence and withdrawal syndrome with long term use.
Obstetrics: neonatal respiratory depression, especially when the last dose was given 1 to 4 hours before delivery. Naloxone readiness for the neonate is standard, with deliberate delay or avoidance of pethidine as labour approaches.
Interactions
- MAO inhibitors (tranylcypromine, moclobemide, selegiline): absolute contraindication, fatal serotonin syndrome reported, at least 14 day gap
- SSRIs, SNRIs, tricyclic antidepressants, tramadol, linezolid: increased risk of serotonin syndrome, avoid combination or monitor closely
- Benzodiazepines, alcohol, other opioids, barbiturates: additive respiratory depression and sedation, markedly increased risk of fatal respiratory arrest with concurrent use
- Neuroleptics: enhanced central depression
- CYP3A4 inhibitors (ritonavir, itraconazole): higher plasma levels, prolonged effect
- CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): loss of effect
Special Notes
Why no longer routine? Current guidelines of the German Society for Anaesthesia and the WHO no longer recommend pethidine as first or second line in acute pain therapy. Reasons are unfavourable pharmacokinetics, the neurotoxic metabolite, the risk of serotonin syndrome and the availability of better alternatives such as piritramide, morphine, oxycodone and hydromorphone.
Obstetrics: the former routine use of pethidine in labour is no longer recommended. Modern alternatives such as epidural analgesia, patient controlled remifentanil or breathing techniques are more effective and safer for mother and child.
Long term therapy: pethidine is unsuitable for chronic pain therapy. Accumulation of norpethidine leads to neurotoxic effects that can trigger seizures. In chronic pain other opioids are preferred.
Pregnancy: single doses in labour are possible, but weighed against modern methods. Breastfeeding: passage into breast milk, avoid repeated doses in nursing mothers. Driving: for at least 24 hours after a single dose do not drive.
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Frequently Asked Questions
Why is Dolantin no longer the standard today?
The metabolite norpethidine accumulates with repeated dosing and can trigger seizures. The short analgesic duration fits poorly with clinical pain therapy, and the risk of serotonin syndrome in combinations is high. Modern alternatives such as piritramide, morphine or fentanyl offer better efficacy and a more favourable safety profile.
When is pethidine still deliberately used today?
The classic indication is postoperative shivering, which is promptly relieved by 12.5 to 25 mg intravenously. At this low single dose the drawbacks are negligible. In individual cases pethidine is also used for cold or fever chills during chemotherapy.
Why is the combination with antidepressants so dangerous?
Pethidine inhibits serotonin reuptake. In combination with MAO inhibitors, SSRIs, SNRIs or tramadol, a serotonin syndrome may develop, with high fever, muscle rigidity, seizures and cardiovascular collapse. The combination is absolutely contraindicated, or only possible under the strictest supervision.
May I receive pethidine during labour?
Historically pethidine was standard labour analgesia; today German clinics increasingly replace it with epidural analgesia or patient controlled remifentanil. When pethidine is used, it is given as early in labour as possible to avoid respiratory depression in the neonate.
Sources
- EMA, European Medicines Agency
- AWMF, Guidelines on Acute Perioperative Pain Therapy
- Gelbe Liste, Pethidine active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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