Overview
This lecture covers opioid analgesics: their historical role as the first effective drugs, how they act in the CNS to relieve pain, the receptor subtypes involved and drug selectivity across them, pharmacokinetic differences between agents, tolerance, a survey of clinically important opioids (including the codeine/heroin prodrug pathways to morphine), the mixed-mechanism drugs tramadol and tapentadol, and finally cannabinoids as an adjunct/alternative for pain.
Opium and Morphine: Historical Context
In the early 20th century, doctors had no antibiotics, dangerous anaesthesia, and no effective or safe drugs for diabetes, the heart, osteoporosis, cancer, asthma, arthritis, immune disorders or epilepsy. Available tools were limited to some surgical instruments, bandages, antiseptic, and morphine, making opium/morphine the first truly effective drug of the era. Morphine occurs naturally in the opium poppy. Historically, opioids (including heroin) were sold unregulated in products such as cough remedies, teething syrups for infants, and “soothing syrups,” reflecting a period before controls on opioid-containing preparations.
What Are Opioids?
- Drugs that act on opioid receptors, which are the receptors for morphine.
- Structurally diverse: endogenous opioids are peptides, while clinically used opioids (morphine, oxycodone, hydrocodone, fentanyl, etc.) are structurally distinct small molecules that also act at these receptors.
Actions and Effects of Opioids
Key pharmacological actions:
- Analgesia
- Cough suppression
- Sedation and anxiolysis
- Depression of respiration (the main cause of death from opioid overdose)
- Nausea and vomiting
- Gastrointestinal immobility: opioids relieve diarrhoea (e.g. loperamide) but cause pain/discomfort from reduced motility (treated with laxatives), and affect absorption of other oral drugs.
Desirable vs undesirable effects:
| Desirable | Undesirable |
|---|---|
| Analgesia | Respiratory depression |
| Cough suppression | Nausea |
| Euphoria | Euphoria |
| Sedation | Sedation |
| Reduced gut motility (treat diarrhoea) | Reduced gut motility (constipation) |
| Dependence | |
| Histamine effects (rare) |
Note that euphoria and sedation appear on both sides: the same effect can be desirable or undesirable depending on context.
Opioids and Pain Management
- Opioids are reserved for moderate to severe pain on the WHO 3-step pain management scale.
- Severity range covered varies by drug: extremely severe pain (fentanyl, hydromorphone) down to mild/moderate pain (codeine).
- Because of this range, opioids are frontline drugs in pain management.
How Opioids Relieve Pain: Mechanism
Opioids act in the central nervous system (in contrast to local anaesthetics and NSAIDs), altering CNS processing and perception of painful stimuli. Other CNS effects include euphoria, drowsiness and sedation.
Opioid receptors are inhibitory G protein-coupled receptors densely expressed by neurons in key CNS areas. Opioids act at two synaptic sites:
- Pre-synaptic: activation of opioid receptors reduces intracellular cAMP concentration, decreases calcium ion influx, and thereby inhibits release of excitatory neurotransmitters (glutamate, substance P), reducing pain signal transmission.
- Post-synaptic: opioid-receptor binding evokes hyperpolarisation of the neuronal membrane (via opening of potassium channels), which decreases the probability of generating an action potential.
At the receptor level: opioid receptors couple through Gi/Go proteins, which open potassium channels (causing post-synaptic hyperpolarisation and inhibition of action potential formation) and inhibit opening of calcium channels in pre-synaptic neurons (inhibiting transmitter release).
Opioid Receptor Distribution Along Pain and Reward Pathways
Enkephalins released from neurons of the descending pathway activate opioid receptors and inhibit pain signals. Opioid receptor-dense sites include the dorsal horn of the spinal cord (receiving peripheral pain input via the dorsal root ganglion), the dorsal raphe nucleus/periaqueductal grey, and reward/pleasure-related regions including the ventral tegmental area, hypothalamus, nucleus accumbens, and nucleus raphe magnus, as well as a cortical region (insular cortex).
The slide for this diagram has a ghosted/duplicate layer of text partially overlapping the main caption (something like "Opioid receptors ... Gi/o ... inhibit neuronal depolarisation"); only the front-layer caption was fully legible in the transcript.
Opioid Receptor Subtypes (μ, δ, κ)
Relative involvement of each receptor subtype in different effects:
- Analgesia: supraspinal (μ +++, δ −?, κ −), spinal (μ ++, δ ++, κ +), peripheral (μ ++, δ −, κ ++)
- Respiratory depression: μ +++, δ ++, κ −
- Pupil constriction: μ ++, δ −, κ +
- Reduced GI motility: μ ++, δ ++, κ +
- Euphoria: μ +++, δ −, κ −
- Dysphoria and hallucinations: μ −, δ −, κ +++
- Sedation: μ ++, δ −, κ ++
- Catatonia: μ −, δ −, κ − (none of the three subtypes strongly mediate catatonia)
- Physical dependence: μ +++, δ −, κ −
Selectivity of Drugs for Opioid Receptors
| Drug | μ | δ | κ |
|---|---|---|---|
| Morphine | +++ | + | + |
| Methadone | +++ | −−− | −−− |
| Fentanyl | +++ | + | −−− |
All clinically relevant opioids act at the μ receptor.
Morphine Pharmacokinetics
- Latency to onset: oral 15-30 minutes; intravenous 15-30 seconds.
- Duration of action: 3-4 hours.
- First-pass metabolism results in poor oral bioavailability: 20-40%.
- Metabolism is hepatic, via phase 1 and phase 2 biotransformations to various metabolites.
Variation in Opioid Pharmacokinetics
- Fentanyl: very fast onset/offset, useful for fine control in anaesthesia/surgery and for breakthrough pain.
- Methadone: long half-life (approximately 15 hours), favoured by some pain specialists for this reason.
- Heroin: crosses the blood-brain barrier rapidly (3-5 minutes) and is deacetylated to morphine.
Tolerance
- Tolerance develops to most pharmacological effects of morphine: analgesia, emesis, euphoria and respiratory depression.
- Addicts may take up to 50 times the normal analgesic dose of morphine with little respiratory depression, but with marked constipation and pupillary constriction (tolerance to these effects develops less).
- Mechanism: desensitisation of μ opioid receptors and long-term adaptive changes in nerve cells.
- Tolerance is a general phenomenon of opioid-receptor ligands, and cross-tolerance occurs between them.
Important Clinical Opioids
- Morphine: very common analgesic in clinical settings.
- Heroin: socially damaging opioid.
- Codeine: commonly prescribed weak opioid.
- Fentanyl: very potent analgesic; associated with an epidemic of abuse in the USA.
- Oxycodone: moderately potent analgesic; associated with “prescription pain” dependence/addiction.
- Methadone: slow pharmacokinetics; used for chronic pain and in heroin addiction treatment.
- Hydromorphone: more potent than morphine, but less potent than fentanyl.
Codeine and Heroin as Pro-drugs for Morphine
- Codeine is demethylated to morphine (the active pathway), and separately demethylated to norcodeine (further converted to norcodeine-6-glucuronide); codeine can also be conjugated directly to codeine-6-glucuronide.
- Heroin is hydrolysed to 6-monoacetylmorphine, which is further hydrolysed to morphine.
- Morphine itself is converted to morphine-3/6-glucuronide, with morphine-6-glucuronide (M-6-G) being an active metabolite.
Tramadol and Tapentadol
- These are mixed weak μ opioid agonist/noradrenaline reuptake inhibitors: moderately strong analgesics with a decreased risk of respiratory depression compared to full opioid agonists.
- α1 and α2 adrenergic receptors are probably also involved in their action; clonidine (an α2 agonist) is itself analgesic, consistent with this mechanism.
Cannabinoids
- The main active ingredient of cannabis is delta-9-tetrahydrocannabinol (THC), which acts on inhibitory G-protein coupled cannabinoid receptors.
- Good evidence exists for partial relief of mild/moderate pain by THC, delivered as smoked cannabis or as Sativex oromucosal spray.
- There is widespread confusion with low-THC hemp-based products enriched with cannabidiol (CBD); evidence for pain relief by CBD is weak.
- Response to cannabinoids varies between individuals: a minority report substantial pain relief. Some patients report better tolerance of cannabinoids than opioids, and perception of pain changes similarly to opioids (pain feels “more remote”). Some evidence suggests patients with pain resistant to opioids may gain some relief from cannabinoids.
- Clinical trials of Sativex for cancer pain have been disappointing overall.
Two double-blind, randomised, placebo-controlled phase 3 studies (Fallon et al., Br J Pain 2017) found Sativex did not demonstrate superiority over placebo in reducing self-reported pain scores in advanced cancer patients with chronic pain unalleviated by optimised opioid therapy, though the authors noted differences between US and rest-of-world patients warranted further exploration.
Self-test
- Explain, at the level of pre-synaptic and post-synaptic mechanisms, how opioids reduce pain signal transmission in the CNS.
- Distinguish desirable from undesirable effects of opioids, and name two effects that can be classed as either depending on context.
- Describe the metabolic pathway by which codeine and heroin act as pro-drugs for morphine, including any active metabolites formed.
- List the three main opioid receptor subtypes and, for each, state one effect it strongly mediates and one it does not.
- Compare the μ/δ/κ receptor selectivity of morphine, methadone and fentanyl.
- What is the oral bioavailability of morphine and why is it so low?
- A patient on methadone and a patient on fentanyl need their pain adequately controlled with fine, minute-to-minute dose titration during a surgical procedure. Which drug is more suitable and why?
- Describe the receptor-level mechanism underlying opioid tolerance, and give the clinical observation in addicts that illustrates differential tolerance across effects.
- Explain the mechanism of action of tramadol and tapentadol, and state why they carry a decreased risk of respiratory depression compared to typical opioids.
- Distinguish THC from CBD in terms of pain-relief evidence and receptor mechanism.
- What did the Fallon et al. (2017) phase 3 trials conclude about Sativex for cancer pain?
- Why are opioids considered frontline drugs across a wide range of pain severities, according to the WHO pain management scale?
- Predict the likely respiratory effect of a κ-selective agonist compared to a μ-selective agonist, based on the receptor-effect table.
- Integrative: trace the full journey of a nociceptive signal being suppressed by morphine, from receptor binding at the pre-synaptic terminal through to the postsynaptic membrane, and explain how this differs mechanistically from how NSAIDs or local anaesthetics relieve pain.
Answers
Reveal answers
- Pre-synaptically, opioid receptor activation reduces intracellular cAMP, decreasing calcium ion influx, which inhibits release of excitatory neurotransmitters (glutamate, substance P). Post-synaptically, opioid receptor binding causes membrane hyperpolarisation (via Gi/Go-coupled opening of potassium channels), reducing the probability of action potential generation.
- Desirable: analgesia, cough suppression, reduced gut motility (treats diarrhoea). Undesirable: respiratory depression, nausea, reduced gut motility (constipation), dependence, histamine effects. Euphoria and sedation appear as both desirable and undesirable depending on context.
- Codeine is demethylated to morphine (also separately demethylated to norcodeine, then norcodeine-6-glucuronide, and conjugated to codeine-6-glucuronide). Heroin is hydrolysed to 6-monoacetylmorphine, then hydrolysed again to morphine. Morphine itself is converted to morphine-3/6-glucuronide; morphine-6-glucuronide is an active metabolite.
- μ: strongly mediates analgesia, euphoria and physical dependence; does not mediate dysphoria/hallucinations. δ: contributes to spinal analgesia and reduced GI motility; does not mediate euphoria or dependence. κ: strongly mediates dysphoria/hallucinations and sedation; does not mediate respiratory depression or euphoria.
- Morphine: μ +++, δ +, κ +. Methadone: μ +++, δ −−−, κ −−−. Fentanyl: μ +++, δ +, κ −−−. All three are strongly μ-selective; morphine has the broadest activity across δ and κ, while methadone and fentanyl are essentially μ-selective with minimal or negative activity at the other subtypes.
- 20-40%, due to extensive first-pass hepatic metabolism.
- Fentanyl, because it has a very fast onset and offset of action, giving fine control suited to intraoperative titration; methadone’s long half-life (~15 hours) makes it unsuitable for rapid adjustment.
- Tolerance results from desensitisation of μ opioid receptors and long-term adaptive changes in nerve cells. Addicts may take up to 50 times the normal analgesic dose with little respiratory depression, but still show marked constipation and pupillary constriction, showing tolerance develops unevenly across effects.
- Tramadol and tapentadol are mixed weak μ opioid agonists and noradrenaline reuptake inhibitors, with α1 and α2 adrenergic receptors also probably involved (consistent with clonidine, an α2 agonist, being analgesic). Because they are only weak μ agonists rather than full agonists, they carry a decreased risk of respiratory depression.
- THC acts on inhibitory G-protein coupled cannabinoid receptors and has good evidence for partial relief of mild/moderate pain. CBD, found in low-THC hemp products, has weak evidence for pain relief and is often confused with THC-containing products.
- Sativex did not demonstrate superiority to placebo in reducing self-reported pain scores in advanced cancer patients with chronic pain unalleviated by optimised opioid therapy, though differences between US and rest-of-world patients warranted further exploration.
- Because opioids are effective across a wide severity range, from extremely severe pain (fentanyl, hydromorphone) to mild/moderate pain (codeine), covering the moderate-to-severe end of the WHO 3-step scale.
- A κ-selective agonist would be expected to cause less respiratory depression than a μ-selective agonist, since μ receptors are strongly linked to respiratory depression (+++) while κ receptors are not (−).
- Morphine binds pre-synaptic opioid receptors on the afferent C-fibre terminal, reducing cAMP and calcium influx, which inhibits release of glutamate and substance P into the synapse. It also binds post-synaptic receptors on the dorsal horn neuron, opening potassium channels and hyperpolarising the membrane, reducing the likelihood of an action potential and thus of nociceptive signal propagation. This is a CNS-based mechanism altering processing and perception of pain, in contrast to local anaesthetics (which block nerve conduction peripherally) and NSAIDs (which act on peripheral inflammatory mediator production), neither of which act centrally on opioid receptors.