Opioids

1. Introduction
2. Pain Pathway Recap
3. Endogenous Opioids and Their Receptors
4. The WHO Analgesic Ladder
5. Specific Opioids
   • Morphine
   • Codeine and Dihydrocodeine
   • Tramadol
   • Oxycodone
   • Fentanyl
   • Methadone
   • Buprenorphine
   • Naloxone
6. Side Effects of Opioids
7. Tolerance, Dependence and Addiction
8. Opioid Overdose
9. Prescribing Practicalities
10. Summary
11. Drug Summary Table
12. Quiz

• Opioids exploit the body's natural opioid receptors: mu (MOP), delta (DOP) and kappa (KOP). The main target is the mu (MOP) receptor, where most clinical effects originate.
• Effects are mediated by G_i-coupled inhibition (the receptor switches on an inhibitory G protein inside the cell). This lowers cyclic AMP (cAMP, an internal cell signal that drives activity), opens potassium (K⁺) channels and closes calcium (Ca²⁺) channels. The result is less neurotransmitter release in pain pathways.
• Opioids range from weak (codeine) through standard (morphine, oxycodone) to ultra-potent (fentanyl). Buprenorphine is a partial agonist (it activates the receptor less than a full agonist, even when every receptor is occupied). It is used in opioid substitution therapy (a prescribed, longer-acting opioid taken in place of street opioids). Naloxone is a competitive antagonist (it occupies the receptor and blocks the opioid) used in overdose.
• The signature side effects are respiratory depression (slow, shallow breathing), constipation, sedation, nausea and miosis (small, "pinpoint" pupils). They are predictable from where MOP receptors are found. The cause of death in opioid overdose is almost always respiratory depression; the antidote is naloxone.

Introduction

Opioids are among the most powerful analgesics (painkillers) in routine clinical use, but they also cause significant preventable harm in the UK. In England, hospital admissions from the harmful use of opioids rose from 10,805 in 2008 to 16,091 in 2018. In 2025, over two in five of all drug-poisoning deaths registered in England and Wales (2,324 of 5,519 deaths, or 42.1%) involved opiates or opioids. Understanding the pharmacology is therefore as much about understanding the harms as the benefits.

This article assumes the basic neuroscience covered in Action Potentials and the receptor pharmacology in Pharmacodynamics.

Pain Pathway Recap

The distinction between nociception (the sensory neural traffic generated by tissue damage) and pain (the conscious, emotional experience that follows) is foundational. Drugs can act at any point along the pathway:

1. Nociceptors (pain-sensing nerve endings) in skin, muscle and the internal organs (viscera) are stimulated by tissue damage. They are also stimulated by inflammatory mediators, which are chemicals released by damaged tissue (bradykinin, prostaglandins, histamine and hydrogen ions).
2. Nociceptors release substance P and glutamate, chemical messengers (neurotransmitters) that pass the pain signal on. The first nerve cells in the chain, called primary afferents (afferent means carrying signals towards the spinal cord), carry the signal in.
3. Afferent fibres are of two main types:
   • Aδ (A-delta) fibres: thinly myelinated (with a thin insulating myelin sheath), fast, carrying sharp, well-localised "first" pain.
   • C fibres: unmyelinated, slow, carrying dull, throbbing "second" pain.
4. Afferents synapse on second-order neurones (the next nerve cells in the chain) in the dorsal horn. This is the back part of the grey matter of the spinal cord, arranged in layers called laminae. Lamina II is also known as the substantia gelatinosa.
5. Second-order neurones decussate (cross to the opposite side) at the spinal level and ascend in the spinothalamic tract (the pathway from the spinal cord to the thalamus).
6. The signal synapses again in the thalamus on third-order neurones.
7. Third-order neurones project to the somatosensory cortex (postcentral gyrus), the part of the cortex that receives touch and pain sensation, for conscious perception. They also project to limbic regions (brain areas that handle emotion) for the emotional component.

Two key sites of endogenous modulation (the body's own pain control):

• The periaqueductal grey matter (PAG) is an area of grey matter in the midbrain (the upper brainstem). It projects descending inhibitory fibres to the dorsal horn, mediated by serotonin, noradrenaline and endogenous opioids. Opioid analgesics work in part by activating this descending inhibitory system.
• At the spinal level, the substantia gelatinosa contains interneurones that gate the transmission of pain signals (the basis of the "gate theory" of pain). Interneurones are short nerve cells that connect other nerve cells within the spinal cord.

Endogenous Opioids and Their Receptors

The body produces three families of endogenous opioid peptides:

• β-endorphins: primarily MOP agonists; major analgesic role.
• Enkephalins: primarily DOP agonists.
• Dynorphins: primarily KOP agonists.

The corresponding opioid receptors are G-protein coupled receptors, all coupled to G_i, an inhibitory G protein. Activation reduces the activity of adenylate cyclase (the enzyme that makes cAMP, an internal cell signal that normally drives activity), so cAMP levels fall. Downstream, K⁺ channels open and Ca²⁺ channels close. This produces presynaptic and postsynaptic inhibition (inhibition on both the sending and receiving side of the synapse) with reduced neurotransmitter release.

• MOP (μ, mu) receptor (the mu opioid peptide receptor): the principal target for clinical analgesia. It mediates analgesia, respiratory depression, euphoria, miosis, constipation and physical dependence, so most opioid effects come from this receptor.
• DOP (δ, delta) receptor: analgesia, mood effects.
• KOP (κ, kappa) receptor: spinal analgesia, dysphoria (an unpleasant low mood), miosis, diuresis (increased urine output).
• NOP (the nociceptin receptor, named after the peptide that activates it): the most recently discovered; its role in adjusting (modulating) pain signalling is complex.

The WHO Analgesic Ladder

The WHO analgesic ladder is a long-standing framework for choosing analgesic strength. It was originally devised for cancer pain but is widely applied. Current UK guidance is more flexible than a strict series of steps, as described below:

Step 1: Non-opioid: paracetamol ± NSAID (non-steroidal anti-inflammatory drug, such as ibuprofen)
Step 2: Weak opioid: codeine, tramadol, dihydrocodeine, ± non-opioid
Step 3: Strong opioid: morphine, oxycodone, fentanyl, ± non-opioid
+ Adjuvants (extra drugs that help pain but are not painkillers in the usual sense) at any step (e.g. amitriptyline or gabapentin for neuropathic pain, which is pain from nerve damage)

Step 2 is not always necessary in cancer pain. NICE (CG140) advises starting oral morphine when a strong opioid is needed in advanced and progressive disease. NICE Clinical Knowledge Summaries (CKS) say step 2 can be omitted when this is clinically appropriate.

Chronic primary pain is long-term pain with no clear underlying condition, or pain out of proportion to any injury or disease. For this, NICE (NG193) advises that opioids should not be started.

Diagram: The WHO analgesic ladder. Climb up if pain remains uncontrolled; combine with non-opioid analgesia and adjuvants at every step.

Specific Opioids

Morphine

The reference opioid against which others are compared. Morphine is a strong full agonist at the MOP receptor.

Pharmacokinetics (what the body does to the drug: absorption, metabolism and excretion):

• Oral bioavailability (the fraction of a dose that reaches the blood) is ~30%, because of extensive first-pass metabolism (breakdown in the liver before the drug reaches the rest of the body); IV gives 100%. That arithmetic gives an oral-to-IV ratio of about 3:1. In practice, the BNF and NICE CKS conversion tables convert oral to subcutaneous or IV morphine at about 2:1 (for example, 30 mg oral morphine is equivalent to about 15 mg subcutaneous morphine), so use the tables when converting.
• Crosses the blood-brain barrier (the tight lining of the brain's blood vessels, which limits what can enter the brain) slowly, because it is relatively hydrophilic (water-loving) and so crosses fatty membranes less easily. It also crosses the placenta and reaches breast milk.
• Metabolised in the liver by glucuronidation (the liver attaches a glucuronide group to the drug). This produces two main metabolites (the products made as the body breaks the drug down). Morphine-3-glucuronide (M3G) is neuroexcitatory (it stimulates nerve cells) and is possibly responsible for myoclonus (sudden muscle jerks) and hyperalgesia (increased sensitivity to pain). Morphine-6-glucuronide (M6G) is analgesic and more potent than morphine itself.
• Both metabolites are renally excreted, which is why morphine accumulates and toxicity can develop in renal impairment.

Morphine is used for moderate-to-severe acute pain, post-operative pain, cancer pain, and breathlessness in advanced palliative care.

Codeine and Dihydrocodeine

Codeine is a weak MOP agonist with around 1/10 the analgesic potency of morphine. It is a pro-drug (inactive until the body converts it into the active drug) that must be converted to morphine by CYP2D6, an enzyme in the liver. Pharmacogenetic variability (differences between people in how their genes affect drug response) therefore strongly influences efficacy and toxicity.

• Poor metabolisers (people whose CYP2D6 enzyme works poorly, about 7 to 10% of people of white European ancestry, with the proportion varying with ethnic origin) get little analgesia.
• Ultra-rapid metabolisers (people whose enzyme works unusually fast) can develop morphine toxicity from standard doses. The MHRA (Medicines and Healthcare products Regulatory Agency, the UK medicines regulator) advises that codeine is contraindicated (must not be used) in three groups. These are people known to be ultra-rapid metabolisers, breastfeeding mothers (codeine passes into breast milk and can harm the baby) and children under 12. In 12 to 18-year-olds it should be used only for acute moderate pain that other painkillers such as paracetamol or ibuprofen alone cannot relieve.
• Fluoxetine, paroxetine and other CYP2D6 inhibitors reduce codeine's analgesic effect.

Beyond the CYP2D6 warning, the MHRA also restricts codeine in two other situations. First, codeine is contraindicated (do not give it) to any child under 18 after tonsillectomy or adenoidectomy (removal of the tonsils or adenoids) for obstructive sleep apnoea (repeated blocking of the airway during sleep). Second, codeine is not recommended for 12 to 18-year-olds whose breathing may be compromised. Examples are a neuromuscular disorder, a severe heart or lung condition, a chest infection, major trauma or extensive surgery.

Codeine is also used as an antitussive (cough suppressant) and antidiarrhoeal (to treat diarrhoea).

Dihydrocodeine has similar potency and a similar profile. Unlike codeine, it is itself an opioid and does not need CYP2D6 to be converted into an active drug. CYP2D6 does convert part of each dose into dihydromorphine (another opioid), so poor metabolisers make much less of it, although their dihydrocodeine blood levels are the same.

Tramadol

Tramadol is an unusual drug with a dual mechanism:

• Weak MOP agonist (its main metabolite is more active than tramadol itself).
• Inhibitor of serotonin and noradrenaline reuptake. Nerve endings take these messengers back up, which ends their action, so blocking this keeps them active for longer. This produces a non-opioid analgesic action via descending inhibitory pathways.

The serotonergic activity creates the risk of serotonin syndrome (toxicity from too much serotonin, with agitation, fever and tremor). The risk rises when tramadol is combined with SSRIs (selective serotonin reuptake inhibitors, a type of antidepressant), MAOIs (monoamine oxidase inhibitors, another type of antidepressant), triptans (migraine drugs) or linezolid (an antibiotic). Tramadol also lowers the seizure threshold (it makes seizures more likely). In epilepsy, use it only if there are compelling reasons, and do not use it in uncontrolled epilepsy.

Oxycodone

Oxycodone is a strong MOP agonist with a similar effect profile to morphine but about 1.5 to 2 times as potent orally (equivalence figures are only approximate). Often used as the alternative when morphine is poorly tolerated, and is the standard strong opioid in some hospital pain regimens.

Fentanyl

Fentanyl is highly lipophilic (fat-loving, so it crosses membranes quickly), around 100 times more potent than morphine, and crosses the blood-brain barrier rapidly. It is available as an IV bolus (a single quick injection), a transdermal patch (absorbed through the skin), sublingual and buccal tablets (dissolved under the tongue or between the gum and cheek), a buccal lozenge, and an intranasal spray.

• After an IV dose, fentanyl quickly moves out of the blood into fat and other tissues (redistribution), which shortens the effect of a single small bolus. It is then cleared much more slowly (terminal elimination), so repeated doses or infusions can prolong its effects. The half-life (the time for the blood level to fall by half) of the brief redistribution phase is much shorter than the half-life of elimination.
• Metabolised by CYP3A4 (a liver enzyme). It is generally considered safer than morphine in renal impairment (reduced kidney function) because it has no active renally cleared metabolite. The BNF (British National Formulary, the UK prescribing reference) still advises caution.
• Causes less histamine release than morphine, so less hypotension.

Standard uses are induction of anaesthesia (starting a general anaesthetic), intra-operative analgesia (pain relief during surgery) and breakthrough cancer pain in patients already taking regular opioids (sudden pain that gets through regular pain control). It is also used for chronic stable pain via patch, but only after the patient is opioid-tolerant.

Methadone

Methadone is a synthetic full MOP agonist with a long and variable half-life (15-60 hours) and oral bioavailability around 80%. It also antagonises (blocks) the NMDA (N-methyl-D-aspartate) receptor, a glutamate receptor involved in pain signalling. The prolonged half-life makes it useful in opioid substitution therapy for opioid use disorder (harmful, compulsive opioid use), and a useful option in chronic cancer pain unresponsive to other opioids.

Methadone also prolongs the QT interval (a part of the ECG; a long QT interval can cause dangerous heart rhythm disturbances) at higher doses, which is a meaningful prescribing concern.

Buprenorphine

Buprenorphine is a partial agonist at the MOP receptor with very high affinity (it binds tightly to the receptor). As a result, its dose-response curve flattens at higher doses. Its respiratory depression reaches a ceiling that full agonists do not have, although in healthy volunteers its pain relief kept increasing with dose. This is one reason it is used in community opioid use disorder treatment. The ceiling is not a guarantee of safety: buprenorphine can still cause fatal respiratory depression, especially when combined with benzodiazepines or similar drugs. NICE (technology appraisal TA114) says methadone and buprenorphine are both options, to be chosen case by case. If both are equally suitable, NICE says methadone should be prescribed as the first choice. Because of this high affinity, naloxone reverses its effects only partially. Like fentanyl, buprenorphine is generally considered a safer choice than morphine in renal failure, but the BNF advises caution in severe renal impairment.

Routes: sublingual tablet (Temgesic; Zubsolv, which also contains naloxone), film placed under the tongue or in the cheek (Suboxone, which also contains naloxone), transdermal patch (BuTrans), oral lyophilisate (Espranor, a freeze-dried tablet that dissolves on the tongue) and long-acting subcutaneous injection (Buvidal, given weekly or monthly). Long half-life (~30 hours).

Naloxone

Naloxone is a competitive opioid antagonist (it competes with opioids for the same receptor and blocks them) with high MOP affinity. It is used to reverse opioid-induced respiratory depression in overdose. It is given intravenously (or intramuscularly, or intranasally in community kits supplied to drug users and their families).

Its short half-life (60-120 minutes) is a critical prescribing point. If the opioid that was taken is long-acting (e.g. methadone), repeated doses or an infusion of naloxone may be needed. The same applies to sustained-release preparations (tablets or patches that release the drug slowly over many hours). Without this, respiratory depression can return once the naloxone wears off.

Side Effects of Opioids

Predictable from MOP receptor distribution. The classical effects:

• Respiratory depression: reduced sensitivity of the medullary respiratory centre (the breathing control centre in the medulla, part of the brainstem) to CO₂. The cause of death in opioid overdose.
• Constipation: reduced gut motility (the gut's normal movement), increased anal sphincter tone. Tolerance to this effect does not develop, so everyone starting a strong opioid should be prescribed a regular laxative. Loperamide, a drug that treats diarrhoea, acts on the same gut opioid receptors (covered in Antiemetics and Laxatives).
• Nausea and vomiting: stimulation of the chemoreceptor trigger zone (CTZ, the vomiting trigger area in the brainstem); usually subsides over a few days. If nausea persists, prescribe an antiemetic (a drug that prevents or relieves nausea and vomiting).
• Sedation, particularly on initiation and dose increase.
• Miosis: pinpoint pupils on examination; useful diagnostic clue in overdose.
• Pruritus (itching), especially after neuraxial opioids (given by spinal or epidural injection). MOP receptors play an important part, and the full mechanism is not yet understood.
• Hypotension and bradycardia (low blood pressure and a slow heart rate): vagal stimulation and histamine release.
• Urinary retention.
• Tolerance, dependence and addiction: see below.
• Endocrine (hormonal) effects with long-term use: hypogonadism (low sex hormone levels), with reduced luteinising hormone (LH), follicle-stimulating hormone (FSH) and testosterone.
• Opioid-induced hyperalgesia: paradoxical increased pain sensitivity with prolonged high-dose use.

Preview the Opioids quiz