Dolantine: Medical Uses, Adverse Effects, Interactions, Mechanism of Action, Pharmacokinetics and Addiction Risks

It is a synthetic opioid medication prescribed for pain, which belongs to the class of phenylpiperidine.

Dolantine, also known as meperidine and pethidine, is marketed under the brand name Demerol, among others.

Synthesized in 1939 as a potential anticholinergic agent by the German chemist Otto Eisleb, Otto Schaumann recognized its analgesic properties when working for the German chemical and pharmaceutical industry “IG Farben”.

Dolantine is the prototype of a large family of analgesics including pethidine 4-phenylpiperidines (piminodine, anileridine and others), products (alphaprodine, desmethylprodine, etc.), bemidones (ketobemidone, etc.) and more distant ones, including diphenoxylate and the like.

Dolantine is indicated for the treatment of moderate to severe pain and is administered as a hydrochloride salt in tablets, as a syrup or by intramuscular, subcutaneous or intravenous injection.

For much of the 20th century, dolantine was the opioid of choice for many physicians; in 1975, 60% of the doctors prescribed it for acute pain and 22% for severe chronic pain.

Compared with morphine, it was thought that dolantine was safer, had a lower risk of addiction and was superior in the treatment of pain associated with biliary spasm or renal colic due to its supposed anticholinergic effects.

Later it was discovered that all these are myths, since it carries the same risk of addiction, has no advantageous effects on biliary spasm or renal colic compared to other opioids, and due to its toxic metabolite, norpethidine is more toxic than other opioids, especially during long-term use.

It was discovered that the metabolite of norpethidine has serotonergic effects, so that dolantin could, unlike most opioids, contribute to the serotonin syndrome.

Prior to 2003, it was on the World Health Organization’s List of Essential Drugs, the most effective and safe medicines needed in a health system.

Medical uses of dolantine

Dolantine is used to relieve pain. It is sometimes used as an analgesic for the relief of pain associated with labor and pain before, during and after surgery.

It is the opioid most used in labor, but has fallen out of favor in some countries such as the United States in favor of other opioids, due to its possible drug interactions (especially with serotonergic) and its neurotoxic metabolite, norpethidine.

It is still commonly used in the United Kingdom and New Zealand, and is the preferred opioid in the United Kingdom for use during childbirth. Dolantine is the preferred analgesic for diverticulitis , since it decreases intestinal intraluminal pressure.

Adverse effects

The adverse effects of the administration of dolantine are mainly those of opioids as a class: nausea, vomiting, sedation, dizziness, diaphoresis , urinary retention and constipation . Unlike other opioids, it does not cause miosis due to its anticholinergic properties.

Overdose can cause muscle flaccidity, respiratory depression, obtundation, cold and clammy skin, hypotension and coma. A narcotic antagonist such as naloxone is indicated to reverse respiratory depression and other effects of dolantine.

The serotonin syndrome has been reported in patients receiving concurrent therapy with antidepressant selective inhibitors of serotonin reuptake or monoamine oxidase inhibitors.

Convulsive seizures that are sometimes observed in patients receiving chronic parenteral dolantin have been attributed to the accumulation in plasma of the metabolite norpethidine. The deaths occurred after an overdose of oral or intravenous dolantine.

Interactions of dolantine with other medications

It is likely that dolantine may also interact with other medications, such as muscle relaxants, some antidepressants, benzodiazepines, and ethanol. Also with the monoamine oxidase inhibitors.

Such patients may suffer agitation, delirium, headache, seizures and / or hyperthermia. Fatal interactions have been reported including the death of Libby Zion . It is believed to be caused by an increase in brain concentrations of serotonin.

Mechanism of action

Like morphine, dolantine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.

Dolantine is often used in the treatment of post-anesthetic tremors. The pharmacological mechanism of this antiepileptic effect is not fully understood, but may involve the stimulation of κ opioid receptors.

Several dolantine analogues such as 4-fluoropethidine have been synthesized which are potent inhibitors of the reuptake of the monoamine neurotransmitters dopamine and norepinephrine via the dopamine transporter and the norepinephrine transporter.

It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.

Other prescription opioids are more likely to be abused, perhaps because of their rapid onset of action.

Especially serious side effects of dolantine among opioids-serotonin syndrome, seizures, delirium, dysphoria, tremor-are due primarily or entirely to the action of its metabolite, norpethidine.

Pharmacokinetics

The toxic effects mediated by metabolites can not be counteracted by opioid receptor antagonists such as naloxone or naltrexone, and are probably mainly due to the anticholinergic activity of norpethidine, probably due to its structural similarity to atropine, although its pharmacology has not been explored thoroughly.

The neurotoxicity of dolantine metabolites is a unique feature of dolantine compared to other opioids. The metabolites of Pethidine are conjugated with glucuronic acid and excreted in the urine.

Addiction risks

Due to the risks of opioid addiction, abuse and misuse, even at the recommended doses, reserve therapy for use in patients for whom alternative treatment options (eg, non-opioid analgesics) have not been tolerated or not tolerate, have not provided adequate analgesia, or are not expected to provide adequate analgesia.

In the data from the US Drug Abuse Warning Network. UU., Mentions of the dangerous or harmful use of dolantine decreased between 1997 and 2002, unlike increases in fentanyl, hydromorphone, morphine and oxycodone.

The number of dose units of dolantine reported as lost or stolen in the USA. UU It increased 16.2% between 2000 and 2003, from 32,447 to 37,687.

Dolantine control

Dolantine is listed in Annex II of the Controlled Substances Act of the United States of 1970 as a narcotic drug under the controlled substances code number 9230, with an aggregate manufacturing quota of 6250 kilograms as of 2014.

The ratio of conversion of free bases to salts includes 0.87 for the hydrochloride and 0.84 for the hydrobromide.

Intermediates A, B and C in the production of dolantine are also controlled, with a code number of controlled administrative substances of 9232 for A (with a quota of 6 grams) and 9233 being B (11 grams quota) and 9234 being C (6 grams quota).

It is included in the list of the Single Convention for the Control of Narcotic Substances of 1961 and is controlled in most countries in the same way as morphine.