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Historically, the term narcotic was used to refer to any psychotropic drug with numbing, sedating, or paralysing properties. Its primary use is now outside of medicine: governments use it as a classification of controlled and/or illicit opioid and non-opioid drugs. “Narcosis” remains in medical use to describe the sedative and depressant adverse effects of opioid medicines.

This note will mostly deal with opioids, the natural, synthetic, and semisynthetic derivatives of opium. In law, medicines such as cocaine, the amphetamines, and the psychedelics are also referred to as narcotics. Few of these will be discussed.

Opiates

Opium

Opium is produced by scoring the poricidal seed capsule of the opium poppy (Papaver somniferum) and collecting the resultant latex; it is rich in opiates, primarily the phenanthrenes morphine, codeine, and thebaine.

Opium has been in use for thousands of years, and predates Christ by over 3000 years… It has a storied history and has been involved in more than one war. Classically, opium is smoked from a specialised pipe held over a an opium lamp. A small pill of opium is placed in the bowl of the pipe and the heat vaporises the opiate compounds for inhalation, as one might imagine, this doesn’t treat the lungs well.

It seems to have gone rather out of fashion, it seems one common tincture of opium, paregoric, is still around. Laudanum, another tincture exists only in the history books. Recipes abound, and you could probably make it for yourself if you have no regard for the law.

Morphine

The prototypical opiate and the first-line choice where a “strong opioid” is required. It remains the standard against which other opioid are compared. Morphine can be synthesised in the laboratory, but much of it is still produced by farming the opium poppy. The alkaloids are now extracted from “poppy straw” rather than the collection of the latex.

Morphine was discovered to be one of the active alkaloids in opium by Friedrich Sertürner in 1804 (or perhaps 1803). He called it morphium after the Greek god of sleep and subsequently became addicted to it, proclaiming it was his duty to attract attention to the terrible effects of his new substance. It first came to market in 1817, and was popularised ten years later by what would become the Merck Group (not Merck & Co.).

The morphine metabolites morphine-6 and morphine-3 glucuronide are renally excreted and may accumulate in the CKD patients causing respiratory depression and neuroexitation respectively. For this reason, morphine is not the first line

Codeine

Despite the fact that codeine naturally occurs in the poppy, most of it is now synthesised from morphine. It is referred to in medicine as a “weak opioid”; codeine itself has a poor affinity for the μ-opioid receptor and almost all of its analgesic action comes from its metabolism into codeine-6-glucuronide and morphine.

There is significant genetic variety in codeine metabolism. Depending on the individual compliment of CYP2D6, metabolism from codeine to morphine may be extensive or quite poor. The “weak opioid” effects of codeine itself are probably similar despite limited metabolism is these patients.

Codeine must not be given intravenously, it precipitates mast cell degranulation and quite significant histamine release and can cause anaphylactoid reactions.¹

Thebaine

A morphinan alkaloid also collected in reasonable amounts from Papaver bracteatum. It is not useful as a medicine but it does provide a good reagent for the synthesis of many of the semi-synthetic opioids. It is said to be a CNS stimulant. In high enough doses it can produce toxicity similar to that of strychnine.

Oripavine

The precursor to the Bentley compounds (buprenorphine and etoprhine, among many others), orpavine has a similar potency to morphine but produces adverse effects that make it unsuitable for medical use. It has a similar toxidrome to thebaine. Fortunately, not much of it is found in opium as it comes mostly from Papaver orientale and Papaver bracteatum.

Semi-synthetic opioids

Dihydrocodeine

Whereas polymorphisms in CYP2D6 lead to unpredictable efficacy of codeine, dihydrocodeine (DHC, 7,8-dihydrocodeine) has more predictable analgesic effect; its transformation into dihydromorphine as also catalysed by CYP2D6 but it would seem that DHC itself is responsible for most of its effect.

Unfortunately, in New Zealand, it is only available as a modified release formulation. As with codeine, intravenous administration of DHC is dangerous.

Oxycodone

Best known as Oxycontin, which is a sustained release formulation, oxycodone has about 1.5-2 times the potency of morphine. It had already been in clinical use for several decades by the time 1995 rolled around and Purdue Pharma fanned the flames of the brewing opioid crisis. There is no shortage of information on the opioid crisis (both in the USA and globally), but let it be said that in the years following the introduction of Oxycontin, opioid prescribing ballooned and more people started dying. Purdue Pharma went out of business after being fined many billion dollars for what it had done.

Oxycodone is preferred over morphine in patients with poor renal function because of its extensive hepatic metabolism. The primary metabolite is noroxycodone which has a weaker affinity and lower potency at the μ-opioid receptor, as well as reduced passage across the blood brain barrier; it accounts for 70% of the metabolic products of oxycodone. Noroxycodone, and the other oxycodone metabolites are renally excreted: there is still a moderate risk of accumulation, particularly in patient with very poor renal function.

Diamorphine (Heroin)

An acetylated form of morphine brought to market under the name Heroin by Bayer in 1898. Diamorphine (3,6-diacetylmorphine) has two acetylene groups that make it lipophilic and allow it to rapidly cross the blood brain barrier. When administered parenterally (particularly intravenously), much of the first pass metabolism is skipped as the drug rapidly enters the central nervous system where it is metabolised. This delivery of diamorphine to the brain allows for much higher concentrations of heroin, its potent deacetylated metabolite 6-monoacetylmorphine, and morphine itself.

Its pharmacology and potency have led it into its niche as a drug of abuse. Similarly to codeine and dihydrocodeine, intravenous injection of diamorphine produces histamine release which is partially responsible for the immediate high.

Hydrocodone

Used almost exclusively by the Americans, hydrocodone is stronger than codeine and is less potent or similar in potency to morphine depending on the route of administration. When given orally, morphine and hydrocodone are about equanalgesic.

Hydromorphone

With 6 times the potency of morphine, one can see why the patients on American medical television shows love Dilaudid. Hydromorphone is not metabolised by the cytochrome P450 system, instead it undergoes glucuronidation to form, almost exlusivley, hydromorphone-3-glucuronide which has the same neuroexitatory affects as its morphine counterpart and is excreted in the urine.

Etorphine

This dangerous veterinary medicine is said to come packed for sale together with its antidote. The available datasheets (for Immobilion, Captivon 98, and Large Animal Etorphilon) suggest this is false. It has largely fallen out of routine use in veterinary practice, but it retains a niche for the capture and sedation of large animals.

Etorphine is one of the Bentley compounds and is several thousand times more potent than morphine (depending on the animal of study). The LD50 in humans is estimated to be somewhere between 30-120μg. For this reason, it comes with stern warnings and protocols for use. Naloxone should be readily available in case of human exposure and its veterinary reversal agent, diprenorphine (or naltrexone or naloxone) shall be ready in equal dose.

Buprenorphine

Unlike most of the other opioids discussed herein, buprenorphine is a partial agonist of the μ-opioid receptor. Its high affinity for the receptor displaces other opioids with weaker affinity which can precipitate withdrawal when administered to patients recently dosed with stronger agonists. It is considered an “atypical opioid”.

It may be used to treatment of acute and chronic pain in low doses, but is used primary for the treatment of opioid dependence due to its partial agonism. It is commonly supplied in combination with naloxone which has very poor oral bioavailability, thus when taken by this route it works without antagonism. The combination is used to deter parenteral administration: naloxone by the parenteral route would antagonise the effect of the buprenorphine.

Synthetic opioids

Tramadol

Another atypical opioid. Despite a moment of wilful excitement in the literature, tramadol is not naturally occurring. Tramadol antagonises the μ-opioid receptor as well as inhibiting the reuptake of serotonin and noradrenaline.

Fentanyl

Methadone

Non-opioid narcotics

Alpha-2 adrenergic agonists

Clonidine
Dexmeditomidine

Barbiturates

Benzodiazepines

Ketamine

Compounds that are not narcotics

Globally, the term narcotic has been misappropriated to describe many substances that have no narcotic effect. It is a general term used in legislation to regulate or outlaw drugs. These false “narcotics” will be discussed elsewhere.

Cocaine
Amphetamines
Cannabis
Psilocybin
Lysergic acid diethylamide (LSD)

Docs

Recent Notes

Classifying the narcotics, with a focus on the opioids

Essential drugs and their dosing

Classifying the antipsychotics

Explorer

Classifying the narcotics, with a focus on the opioids

Opiates

Opium

Morphine

Codeine

Thebaine

Oripavine

Semi-synthetic opioids

Dihydrocodeine

Oxycodone

Diamorphine (Heroin)

Hydrocodone

Hydromorphone

Etorphine

Buprenorphine

Synthetic opioids

Tramadol

Fentanyl

Methadone

Non-opioid narcotics

Alpha-2 adrenergic agonists

Barbiturates

Benzodiazepines

Ketamine

Compounds that are not narcotics

Further reading:

Table of Contents

Docs

Recent Notes

Classifying the narcotics, with a focus on the opioids

Essential drugs and their dosing

Classifying the antipsychotics

Explorer

Classifying the narcotics, with a focus on the opioids

Opiates

Opium

Morphine

Codeine

Thebaine

Oripavine

Semi-synthetic opioids

Dihydrocodeine

Oxycodone

Diamorphine (Heroin)

Hydrocodone

Hydromorphone

Etorphine

Buprenorphine

Synthetic opioids

Tramadol

Fentanyl

Methadone

Non-opioid narcotics

Alpha-2 adrenergic agonists

Barbiturates

Benzodiazepines

Ketamine

Compounds that are not narcotics

Further reading:

Footnotes

Table of Contents