The Stronger Painkillers

TL;DR. Opioids are excellent for short-term severe pain and for cancer and palliative care, and poor for chronic non-cancer pain, where trials show they perform no better than non-opioid options while producing tolerance, dependence, and worsened function. Codeine is a prodrug that some people cannot activate and others activate far too well, which is why it is banned in children and in breastfeeding in many countries. The overdose mechanism is respiratory depression, and naloxone reverses it within minutes. Every opioid causes constipation and the tolerance to that never develops.

1. What they are

Drugs acting on opioid receptors (mu, kappa, delta), which are the body's own system for modulating pain, mood, and reward, normally activated by endorphins and enkephalins.

Not opioids, but grouped with strong painkillers:

• Gabapentin and pregabalin (gabapentinoids), for neuropathic pain. Now controlled drugs in the UK because of misuse and because they substantially increase respiratory depression risk when combined with opioids.
• Amitriptyline and duloxetine, first-line for several neuropathic pain conditions, at doses far below those used for depression.

2. How they work

Opioid receptors are G-protein coupled receptors concentrated in the brain, spinal cord, and gut. Activating them:

• Reduces pain transmission in the dorsal horn of the spinal cord
• Alters the emotional response to pain in the limbic system, which is why people on opioids often report that the pain is still there but no longer distressing
• Produces euphoria via dopamine release in the reward pathway, which is the basis of addiction
• Suppresses the respiratory centre in the brainstem, reducing the drive to breathe in response to rising CO₂. This is what kills in overdose
• Slows gut motility profoundly, via receptors in the enteric nervous system
• Suppresses cough, which is why codeine appears in cough medicines

Codeine is a prodrug and this is the single most consequential fact about it. About 10 percent is converted to morphine by CYP2D6, and CYP2D6 activity varies enormously by genetics (Chapter 62):

• Poor metabolisers (roughly 5 to 10 percent of people of European descent) get little or no analgesia. Codeine simply does not work for them, and they are often assumed to be exaggerating.
• Ultra-rapid metabolisers (up to 30 percent in some North African, Ethiopian, and Middle Eastern populations) convert far more, and can reach dangerous morphine levels from a standard dose.

This has killed children. Deaths after tonsillectomy in ultra-rapid metaboliser children, and at least one infant death from a breastfeeding ultra-rapid metaboliser mother, led the FDA, EMA, and MHRA to contraindicate codeine in children under 12, in under-18s after tonsillectomy or adenoidectomy, and in breastfeeding.

3. Dose and use

Illustrative only. Opioid dosing is individualised, and prescription opioids should never be taken other than as prescribed to you.

Codeine (OTC where available, always in combination): 8 to 30 mg with paracetamol, up to four times daily. UK over-the-counter codeine combinations are licensed for a maximum of three days and carry addiction warnings on the pack, a change made in 2009 after concern about dependence developing from over-the-counter use.

Where opioids genuinely belong:

• Acute severe pain: fractures, major trauma, post-operative, renal colic, myocardial infarction.
• Cancer pain and palliative care, where they are indispensable and where opioid-phobia causes real, avoidable suffering. The concerns that dominate the chronic non-cancer pain discussion largely do not apply here.
• Short courses for acute pain that has failed non-opioid treatment.

Where the evidence says they do not belong: chronic non-cancer pain. The SPACE trial (Krebs and colleagues, JAMA 2018) randomised patients with chronic back, hip, or knee pain to opioid or non-opioid therapy for 12 months and found no difference in pain-related function, slightly better pain intensity in the non-opioid group, and more adverse effects with opioids. Systematic reviews of long-term opioid therapy find small analgesic benefit that diminishes with time, alongside substantial harm.

4. Side effects

Very common, and they define the experience:

Opioid-induced constipation deserves emphasis because it is so consistently under-treated. Opioid receptors in the gut slow motility profoundly, and unlike every other side effect, this one does not fade. Anyone on regular opioids needs a laxative from day one, usually a stimulant (senna, bisacodyl) with or without an osmotic agent, not just a bulking agent, which can make things worse (Chapter 71).

Longer-term effects:

• Tolerance: escalating doses for the same relief.
• Physical dependence: withdrawal on stopping. This is expected physiology, not addiction (Chapter 62).
• Opioid-induced hyperalgesia: paradoxical increased sensitivity to pain with long-term use.
• Hypogonadism: reduced testosterone and oestrogen, with fatigue, low libido, and reduced bone density.
• Immune suppression and increased fracture risk from falls.
• Sleep-disordered breathing.

Withdrawal (for the physically dependent) is deeply unpleasant and, unlike alcohol or benzodiazepine withdrawal, is not usually life-threatening: sweating, agitation, muscle aches, cramping, diarrhoea, gooseflesh, yawning, insomnia, and intense drug craving, peaking at 1 to 3 days for short-acting opioids. It should be managed with a supervised taper.

5. Overdose, and what to do

The mechanism is respiratory depression. The brainstem's response to rising carbon dioxide is suppressed, breathing slows and becomes shallow, oxygen falls, and death follows.

Recognise it by the triad:

1. Reduced consciousness or unresponsiveness
2. Slow, shallow, or absent breathing (under about 12 breaths per minute, often much less)
3. Pinpoint pupils

Plus blue or grey lips and fingertips, gurgling or snoring sounds, and limp body.

What to do:

1. Call emergency services immediately.
2. Give naloxone if available.
3. Rescue breaths if trained, and the recovery position.
4. Stay with them. Naloxone wears off before many opioids do.

Naloxone is a pure opioid antagonist that displaces opioids from the receptor and reverses respiratory depression within 2 to 5 minutes. It is available as an intranasal spray or injection, is available without prescription in many countries and free through harm reduction services, and has no potential for misuse and no effect on someone who has not taken opioids. Giving it to someone who turns out not to have overdosed does no harm.

Its half-life is shorter than most opioids, particularly methadone and long-acting formulations, so someone can wake up and then deteriorate again. Repeat doses and hospital observation are needed.

The two highest-risk situations, both counterintuitive:

• After a period of abstinence. Tolerance falls fast, and a dose that was routine before a spell in prison, hospital, or rehab can be fatal. Overdose deaths cluster in the weeks after release from custody.
• Combined with other sedatives. Alcohol, benzodiazepines, gabapentinoids, and sedating antihistamines all add to respiratory depression. A large share of opioid deaths involve more than one drug, and this combination is more dangerous than either alone.

Illicit fentanyl now dominates overdose deaths in North America and is spreading elsewhere. Its potency means that inconsistent mixing in illicit supply produces lethal doses unpredictably. Nitazenes, even more potent, have appeared more recently.

6. Addiction, and the honest framing

The North American opioid crisis has killed hundreds of thousands of people. Its origins are well documented: aggressive marketing of oxycodone in the 1990s built on weak evidence about addiction risk (including a five-sentence 1980 letter to the NEJM, repeatedly miscited as a study), the promotion of pain as "the fifth vital sign," and prescribing incentives, followed by a shift to heroin and then illicit fentanyl as prescription supply was restricted.

Two errors are worth avoiding, and both cause harm:

Underestimating risk. Dependence can develop within weeks of regular use. Risk of persistent use after a first prescription rises sharply with the duration of that initial course, which is why guidance now emphasises short courses and small quantities.

Overcorrecting. Abrupt tapering or discontinuation of long-term opioids in stable patients has been associated with increased risk of overdose and suicide, and the CDC explicitly revised its 2016 guidance in 2022 because it had been applied as rigid policy in ways that harmed patients. Opioid-phobia in cancer and palliative care causes genuine, avoidable suffering.

Opioid use disorder is a treatable medical condition. Opioid agonist treatment with methadone or buprenorphine roughly halves mortality and is the best-evidenced treatment there is. It is not "substituting one addiction for another"; it is the standard of care.

7. Interactions

8. Practical guidance

• Take the lowest dose for the shortest time for acute pain, and step down to paracetamol and an NSAID as soon as you can.
• Start a laxative on day one, not when constipation appears.
• Never drink alcohol with opioids, and never combine with sedatives that were not prescribed together deliberately.
• Do not drive while starting or changing dose. In the UK it is an offence to drive impaired even on a lawfully prescribed medicine.
• Never take anyone else's opioid prescription, and never give yours away.
• Return leftovers to a pharmacy. Unused opioids in home cupboards are a major source of diversion and of accidental paediatric poisoning (Chapter 86).
• If you or someone close to you uses opioids, get naloxone and learn to use it. It is free in many places, harmless if given unnecessarily, and it works.
• Never crush or chew a modified-release opioid tablet. This delivers a day's dose at once and has killed people (Chapter 63).
• Fentanyl patches deserve specific care: heat (hot baths, heating pads, fever) increases absorption substantially and has caused fatal overdoses. Used patches still contain most of the drug and are dangerous to children and pets; fold sticky sides together and dispose of them properly.

9. The bottom line

• Opioids relieve severe acute pain and cancer pain excellently, and in chronic non-cancer pain they perform no better than non-opioid options while causing tolerance, dependence, and reduced function.
• Codeine is a prodrug requiring CYP2D6. Some people get nothing from it; some convert too much. It is contraindicated in children under 12 and in breastfeeding.
• Constipation is the one side effect that never fades. Start a stimulant laxative on day one.
• Overdose kills by respiratory depression. Look for unresponsiveness, slow breathing, and pinpoint pupils. Naloxone reverses it in minutes, is harmless if given unnecessarily, and wears off before the opioid does.
• The two highest-risk situations are restarting after a break, when tolerance has fallen, and combining opioids with alcohol, benzodiazepines, or gabapentinoids.
• Opioid agonist treatment with methadone or buprenorphine halves mortality in opioid use disorder and is the standard of care, not a moral compromise.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Opioid receptor pharmacology and equianalgesic ratios follow standard pain medicine references and the Faculty of Pain Medicine's opioid guidance. CYP2D6 and codeine follows the CPIC guideline and the EMA and FDA restrictions after paediatric deaths, documented in Kelly et al., Pediatrics, 2012. Chronic non-cancer pain evidence is the SPACE trial, Krebs et al., JAMA, 2018, plus Busse et al.'s meta-analysis, JAMA, 2018. Opioid-induced constipation and its lack of tolerance follow standard palliative care references. Opioid-induced hyperalgesia follows Angst and Clark's review. Naloxone pharmacology and community distribution follow WHO guidance and national take-home naloxone programme evaluations. Post-release overdose risk follows Binswanger et al., NEJM, 2007. The opioid crisis origins, including the miscitation of the 1980 Porter and Jick letter, follow Leung et al., NEJM, 2017, and the Purdue litigation record. The CDC's 2022 revision of its 2016 guideline followed evidence that rigid application caused harm, documented by Dowell et al. Opioid agonist treatment mortality reduction follows Sordo et al., BMJ, 2017. Fentanyl patch heat-related overdose follows FDA safety communications. Gabapentinoid reclassification in the UK followed ACMD advice in 2019.

Open questions. How to taper long-term opioid patients safely, and whether tapering improves outcomes at all in stable patients, is genuinely unresolved and current guidance is cautious in both directions.

👉 Next: cold, cough, and flu medicines, where most of what is sold does very little.