Pethidine

Pethidine is a fully synthetic opioid agonist and acts on the CNS and peripheral organs similarly to morphine. Pain perception and transmission are suppressed by pethidine.

Pethidine has a pronounced affinity for the µ-opioid receptors. Its affinity for the δ- and κ-receptors is low. In addition to its strong analgesic effect, pethidine also shows sedative, antitussive as well as respiratory depressant effects (roughly equivalent to morphine). Pethidine lowers the tone of vascular smooth muscle and thus has a blood pressure lowering effect. The drug leads to an increase in heart rate.

Pethidine is well absorbed enterally; therefore oral administration is possible. Maximum plasma concentrations are reached after 1-2 hours. Due to the pronounced first-pass effect, bioavailability is only 48-63% when administered orally. After intramuscular application, maximum plasma concentrations are reached within 15 minutes. The bioavailability is 93-98%. Pethidine is 37-73% bound to plasma protein. Mean half-life: approximately 6.0 H. Elimination half-life: 3.2-8.0 H.

Metabolism: Pethidine is inactivated relatively rapidly in the liver by hydrolysis of the ester group. Pethidine + metabolites are excreted boron predominantly renally. In renal dysfunction, pethidine or its degradation products (e.g. norpethidine) may accumulate.

Pethidine is available in the form of injection solutions, suppositories or orally in the form of drops

Treatment of severe to very severe pain when non-opioid painkillers or weakly acting opioids show no or only insufficient effect. This applies to tumour pain or traumatic pain after accidents and operations. Pethidine is not indicated for the long-term treatment of chronic pain.

Pethidine crosses the placental barrier virtually unhindered and also passes into breast milk. The plasma half-life in newborns is two to seven times longer than in adults. Thus, use of pethidine during pregnancy and childbirth is not recommended. Insufficient experience is currently available.

Breast-feeding: Pethidine and its metabolite norpethidine pass into breast milk and therefore breast-feeding should not be undertaken during treatment with pethidine.

Usual single doses contain between 25 and 150 mg (i.m. and s.c.) or 50 mg (i.v.).

Oral drops (50 mg/ml): The single dose for adults is between 25 and 150 mg of pethidine hydrochloride (10 and 60 drops). The daily dose for adults should not exceed 500 mg of pethidine hydrochloride.

For children over 1 year of age, only the drops are approved. These are dosed depending on body weight. The single dose is 0.6 to 1.2 mg of pethidine hydrochloride per kilogram of body weight (equivalent to 1 to 2 drops per 4 kg of body weight).

Common:

Confusion, mood changes (usually euphoria, occasionally dysphoria); changes in cognitive and sensory performance (e.g., with regard to decision-making as well as perceptual disturbances), dizziness, sedation, respiratory depression.

Occasional:

Increase in amylase and lipase concentrations, increase in liver transaminases.

Hypersensitivity reactions (urticarial exanthema, urticaria, anaphylaxis, possibly including life-threatening shock), flushing, sweating and pruritus due to histamine release (Aníbarro B et al. 2000).

Very rare:

Psychosis

Side effects of unknown frequency:

Tachycardia, bradycardia, hypotensive circulatory reactions, myocardial infarction(Kounis syndrome), tremor, involuntary muscle movements, seizures (especially at higher doses, impaired renal function and increased convulsiveness), visual disturbances, miosis (especially after rapid intravenous administration), bronchospasm, singultus (in each case especially after rapid intravenous administration), nausea, vomiting (in each case especially after rapid intravenous administration), dry mouth, loss of appetite, contraction of the bile ducts and pancreatic duct, disorientation, delirium, sleep disturbances.

Particularly with prolonged use, constipation or micturition problems such as urinary retention may occur due to an increase in smooth muscle tone.

Caution should be exercised when pethidine is administered concomitantly with the following substances/drugs:

Ritonavir may increase the plasma concentration of the metabolite norpethidine.

Phenytoin may increase the hepatic metabolism of pethidine. Concomitant administration results in decreased half-life and bioavailability of pethidine and increased concentration of norpethidine.

Cimetidine reduces the clearance and volume of distribution of pethidine and the formation of norpethidine.

Benzodiazepines: The use of benzodiazepines in combination with opioids may increase the risk of sedation, respiratory depression, coma, and death by reciprocal potentiation of the central depressant effect. Doses and duration of concomitant use should be limited.

Barbiturates: Concomitant use with barbiturates and other centrally depressant pharmaceuticals may result in decreased level of consciousness or respiratory depression due to additive CNS depressant effects.

Alcohol increases the risk of sedation, respiratory depression, coma, and death due to reciprocal potentiation of central depressant effects.

Phenothiazines may increase the risk of hypotension.

Phenobarbital may increase metabolism of pethidine during long-term therapy.

Partial opioid receptor antagonists (pentazocine, nalbuphine, and buprenorphine) may reduce the analgesic effect of pethidine and lead to withdrawal symptoms due to competitive receptor antagonism.

MAO inhibitors: Possible life-threatening interactions on central nervous system, respiratory and circulatory function are possible after premedication with MAO inhibitors within the last 14 days before opioid application.

Serotonergic drugs (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and St. John's wort preparations) may also lead to the occurrence of serotonin syndrome.

• hypersensitivity to pethidine
• concomitant treatment with MAO-inhibitors or within 14 days after the last intake
• severe respiratory insufficiency and pathological conditions in which respiratory centre depression must be avoided
• severe hepatic dysfunction, acute hepatic porphyria, biliary colic, post cholecystectomy syndrome, pancreatitis
• head trauma, increased intracranial pressure
• Supraventricular arrhythmias
• Alcoholism and drug addiction.

Dolantin® 50 mg solution for injection, drops, suppositories; Dolcontral® 100 mg, suppositories; Pethidine-hameln® 50 mg/ml, 1 ml;

Further details on this active substance can be found in the respective specialist information. No traffic ability under pethidine.

1. Aníbarro B et al. (2000) Urticaria induced by meperidine allergy. Allergy 55:305-306.
2. Clark RF et al (1995) Meperidine: therapeutic use and toxicity. J Emerg Med 13:797-802.
3. Latta KS et al (2002) Meperidine: a critical review. Am J Ther 9:53-68.
4. Mather LE et al (1978) Clinical pharmacokinetics of pethidine. Clin Pharmacokinet 3:352-368.
5. Graefe KH et al. Nociceptive system. In: Graefe KH et al (Eds) Pharmacology and Toxicology. Georg Thieme Publisher Stuttgart pp 228-239.