Pethidine

Pethidine is the most widely used opioid in labour and delivery.^[16] It has fallen out of favour in some countries, such as the United States, in favour of other opioids, due to its potential drug interactions, especially with serotonergics, and its neurotoxic metabolite, norpethidine.^[10] It is still commonly used in the United Kingdom and New Zealand,^[17] and was the preferred opioid in the United Kingdom for use during labour, but has been superseded somewhat by other strong semi-synthetic opioids (e.g. hydromorphone) to avoid serotonin interactions since the mid-2000s.^[18]

Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure.^{[19][full citation needed]} Pethidine is the preferred drug for the management of shivering during therapeutic hypothermia, as it provides the greatest reduction in the shivering threshold.^[20]

Before 2003, it was on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[21][22]

The adverse effects of pethidine administration are primarily those of the opioids as a class: nausea, vomiting, dizziness, diaphoresis, urinary retention, and constipation. Due to moderate stimulant effects mediated by pethidine's dopamine and norepinephrine reuptake inhibition, sedation is less likely compared to other opioids. Unlike other opioids, it does not cause miosis because of its anticholinergic properties. Overdose can cause muscle flaccidity, respiratory depression, obtundation, psychosis, cold and clammy skin, hypotension, and coma.^[23][24]

A narcotic antagonist such as naloxone is indicated to reverse respiratory depression and other effects of pethidine. Serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors, or other medication types (see Interactions below). Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumulation in plasma of the metabolite norpethidine (normeperidine). Fatalities have occurred following either oral or intravenous pethidine overdose.^[25][26]

Pethidine has serious interactions that can be dangerous with monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine). Such patients may suffer agitation, delirium, headache, convulsions, and/or hyperthermia. Fatal interactions have been reported including the death of Libby Zion.^[27]

Seizures may develop when tramadol is given intravenously following, or with, pethidine.^[28] It can interact as well with SSRIs and other antidepressants, antiparkinson agents, migraine therapy, stimulants and other agents causing serotonin syndrome. It is thought to be caused by an increase in cerebral serotonin concentrations. It is probable that pethidine can also interact with a number of other medications, including muscle relaxants, benzodiazepines, and ethanol.

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.^[29]

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood,^[30] but it may involve the stimulation of κ-opioid receptors.^[31]

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.^[32] In addition to these opioidergic and anticholinergic effects, it has local anesthetic activity related to its interactions with sodium ion channels.

Pethidine's apparent in vitro efficacy as an antispasmodic agent is due to its local anesthetic effects. It does not have antispasmodic effects in vivo.^[33] Pethidine also has stimulant effects mediated by its inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NET). Pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline, probably as a result of its inhibitory actions on DAT and NET.^[34]

Several analogs of pethidine such as 4-fluoropethidine have been synthesized that are potent inhibitors of the reuptake of the monoamine neurotransmitters dopamine and norepinephrine via DAT and NET.^[35][36] It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.^{[34][36][37][38]}

It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120–150 minutes, although it is typically administered at 4– to 6-hour intervals. Pethidine has been shown to be less effective than morphine, diamorphine, or hydromorphone at easing severe pain, or pain associated with movement or coughing.^[34][36][38]

Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. The especially severe side effects unique to pethidine among opioids—serotonin syndrome, seizures, delirium, dysphoria, tremor—are primarily or entirely due to the action of its metabolite, norpethidine.^[36][38]

Pethidine can be produced in a two-step synthesis. The first step is reaction of benzyl cyanide and chlormethine in the presence of sodium amide to form a piperidine ring. The nitrile is then converted to an ester.^[43]

Pethidine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN 9230 with a 6250 kilo aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride and 0.84 for the hydrobromide. The A, B, and C intermediates in production of pethidine are also controlled, with ACSCN being 9232 for A (with a 6 gram quota) and 9233 being B (quota of 11 grams) and 9234 being C (6 gram quota).^[44] It is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in the same fashion as is morphine.^{[citation needed]}

Pethidine provides analgesia for 60 to 90 minutes in the cat and dog.^[39] Pethidine is less effective in horses, with IV, SC, and IM administration failing to provide thermal antinociception.^[39][45][46] Epidural administration of pethidine into the caudal area provided 4-5 hours of analgesia with no cardiovascular depression and only minor sedation.^[47][39] Due to the short duration of analgesia and side effects pethidine is not commonly used with other opioids being used instead.^[48]

Pethidine is vagolytic but high doses cause bradycardia due to cardiac depression. Pethidine is metabolised by the hepatic enzyme CYP450 via N-demethylation to produce normeperidine. Normeperidine is excitotoxic and can cause myoclonus when too much pethidine is administered. The treatment for these side effects are benzodiazepines. Histamine release following IV administration can cause flare reaction, pruritus, hypersalivation, urination, defaecation, and tachypnoea. IM injection can cause localised oedema and erythema.^[39]

• Libby Zion Law (a case involving phenelzine and pethidine)