PART 4 – Pain treatment

Paracetamol

Pain management is one of the most fundamental skills you will use in clinical practice – whether you work in emergency care, hospitals, general practice, or in acute medicine. Nevertheless, pain management is far more complex than choosing the “right pill.” It requires understanding of:

pharmacology
pathophysiology
interactions
side effect profiles
patient factors
rules and regulations (driver's license, blue prescription, risk of addiction)

This part of the compendium is written to give you a clinically relevant and practically applicable understanding of the most common analgesics. The goal is that you should be able to:

choose the right medication for the right patient
understand why a medication works
know the risks and how to prevent them
use medications safely and effectively
communicate well with patients about pain management

We start with paracetamol, which is the cornerstone of all pain management.

CHAPTER 1 – PARACETAMOL

Paracetamol is one of the most used medications in Norway and globally. It is the first choice for mild to moderate pain and fever, and is used by all age groups. Despite its widespread use, the mechanism is far more complex than previously thought.

This chapter provides a clinically relevant review of the use of paracetamol.

1.1 Mechanism of action – more complex than previously thought

Paracetamol has long been described as a “mysterious” drug because the mechanism was not fully understood. Recent research shows that paracetamol works through several parallel mechanisms, both centrally and peripherally.

1. Central COX inhibition

Paracetamol inhibits the COX enzyme in the CNS (1,2), but not peripherally, which explains why it:

reduces pain and fever
does not have an anti-inflammatory effect

This is confirmed in recent literature.

2. Endocannabinoid modulation via AM404

Paracetamol is metabolized to AM404 (3,4), which:

activates CB1 receptors
activates TRPV1 receptors
inhibits reuptake of anandamide

inhibits reuptake of anandamide

This provides a significant analgesic effect via the brain and spinal cord.

3. Peripheral blockade of sodium channels

AM404 blocks peripheral Nav1.7 and Nav1.8 sodium channels in nociceptive nerve endings (4,5).

This is the same type of channel involved in:

erythromelalgia
certain genetic pain syndromes
the effect of certain local anesthetics

4. Activation of descending serotonergic pain pathways

Paracetamol increases serotonergic activity in the brainstem and spinal cord, which inhibits pain transmission (6,7).

5. Possible COX-3 inhibition

COX-3 is a brain variant of COX-1. Some studies suggest that paracetamol can inhibit COX-3, but this does not explain the entire effect (8,1).

1.2 Pharmacokinetics and clinical effect

Absorption and onset of action

Effect after about 30 minutes
Maximum effect after 1–2 hours
Duration of action 4–5 hours

This makes paracetamol suitable as a basic analgesic.

Metabolism

90% is metabolized via glucuronidation and sulfation, conjugated in the liver
5–10% is metabolized via CYP2E1 to NAPQI (9-11)
NAPQI is detoxified by glutathione

In case of overdose, glutathione stores are depleted → liver damage.

1.3 Dosage

Adults

15 mg/kg per dose
max 4 g/day
A 70 kg adult → max 1 g × 4

Elderly

Consider lower max dose (2–3 g/day) in (12):

low body weight
malnutrition
alcohol overuse
liver disease

Children

15 mg/kg × 4
Maximum 60 mg/kg/day (12)

1.4 Toxicity – why paracetamol can be dangerous

Paracetamol is safe at therapeutic doses but has a narrow toxic window in overdose.

Acute toxicity

150 mg/kg → risk of liver damage
Corresponds to 20 × 500 mg tablets in a 70 kg adult

Chronic toxicity

70–90 mg/kg/day over several days
Common in the elderly, alcoholics, malnourished

Pathophysiology

Overdose → increased NAPQI → glutathione consumption → hepatocellular necrosis
The damage is greatest in zone 3 (centrilobular) (13-15)

1.5 Clinical considerations – when is paracetamol first choice?

Paracetamol is first choice for (12,16,17):

headache
musculoskeletal pain
fever
pain in the elderly
pain in pregnancy
pain in ulcers or risk of bleeding
pain in kidney failure

It is also a basis in multimodal pain management, e.g., postoperatively.

1.6 When is paracetamol not enough?

Paracetamol has limited effect on:

inflammatory pain
neuropathic pain
severe acute pain (18,19)

1.7 Interactions

Paracetamol has few interactions, but:

alcohol increases the risk of liver damage
Enzyme inducers (rifampicin, carbamazepine) increase NAPQI
Warfarin: long-term use can increase INR. Paracetamol inhibits the vitamin K cycle. At higher doses and especially with regular use over several days, reactive metabolites are formed that inhibit the VKOR enzyme – the same enzyme that warfarin blocks. The effect becomes additive → INR rises. Paracetamol metabolites can reduce the liver's production of vitamin K-dependent coagulation factors (II, VII, IX, X), which enhances warfarin's effect. The effect is typically seen with >2–3 g of paracetamol daily over several days, not with occasional use. (20-22)

1.8 Summary

Paracetamol is a safe and effective first choice for mild to moderate pain, with a complex mechanism of action that involves:

central COX inhibition
endocannabinoid modulation
sodium channel blockade
serotonergic pain pathways

It is safe for most patients, but has a narrow toxic window in overdose.

Reference list

Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12(1):46–55.
Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in humans. Clin Pharmacol Ther. 2008;84(6): 725–730.
Högestätt ED et al. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase–dependent arachidonic acid conjugation in the nervous system. J Biol Chem. 2005;280(36):31405–31412.
Mallet C et al. TRPV1 in the periaqueductal gray contributes to paracetamol analgesia via CB1 receptors. Pain. 2010;152(2): 465–474.
Brenner DS et al. Nav1.7 and Nav1.8 contribute to pain processing. Neuron. 2014;82(4): 739–754.
Pickering G et al. Paracetamol and central serotonergic mechanisms. Clin Pharmacol Ther. 2006;79(4): 371–378.
Pini LA et al. Serotonergic descending pathways and analgesia: relevance for paracetamol. Eur J Pharmacol. 1996;308(1): 31–40.
Chandrasekharan NV et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen. PNAS. 2002;99(21):13926–13931.
Prescott LF. Paracetamol pharmacokinetics and metabolism. Clin Pharmacokinet. 1980;5(2): 93–107.
Forrest JA et al. Paracetamol absorption and kinetics. Eur J Clin Pharmacol. 1982;22(2): 121–125.
Lee WM. Acetaminophen hepatotoxicity: clinical overview. N Engl J Med. 2003;349: 474–485.
Drug Handbook. Paracetamol – monograph.
Rumack BH, Matthew H. Acetaminophen poisoning and the nomogram. Pediatrics. 1975;55(6): 871–876.
Larson AM et al. Acetaminophen-induced acute liver failure: results from the U.S. ALF Study Group. Hepatology. 2005;42(6): 1364–1372.
Lee WM. Drug-induced liver injury. N Engl J Med. 2003;349: 474–485.
NICE Clinical Guideline. Pain management in adults.
WHO. WHO Pain Ladder – Cancer Pain Relief.
Derry S et al. Single dose oral paracetamol for acute postoperative pain in adults. Cochrane Database Syst Rev. 2013;Issue 1:CD004602.
Finnerup NB et al. Pharmacotherapy for neuropathic pain. Lancet Neurol. 2015;14(2):162–173.
Whitcomb DC, Block GD. Association of acetaminophen with hepatic injury. JAMA. 1994;272(23):1845–1850.
Thijssen HH et al. Paracetamol and warfarin interaction: mechanisms and clinical relevance. Br J Clin Pharmacol. 2004;57(3): 326–334.
The Drug Handbook. Interactions – Paracetamol.

NSAIDs (non-steroidal anti-inflammatory drugs)

NSAIDs are among the most commonly used analgesics in clinical practice. They are effective for inflammatory pain, musculoskeletal disorders, acute injuries, and fever. At the same time, they are associated with significant side effects, especially with long-term use or in vulnerable patients.

This chapter provides a clinical and pharmacological understanding of the use of NSAIDs.

2.1 Mechanism of action – COX inhibition and prostaglandins

NSAIDs work by inhibiting the enzymes COX-1 and COX-2, which convert arachidonic acid into prostaglandins and thromboxanes (1-5).

COX-1 ("the housekeeping enzyme")

COX‑1 is the “housekeeping enzyme” because it is produced continuously and maintains normal protective functions in the body. It produces prostaglandins that protect the stomach lining, maintain kidney blood flow, and contribute to normal platelet function. Inhibition of COX‑1 therefore explains much of the side effect profile of traditional NSAIDs, especially stomach ulcers and bleeding risk.

Produces prostaglandins that are important for:

protection of the stomach lining
maintenance of kidney blood flow
platelet function (TXA₂)

COX‑2 (“inflammatory enzyme”)

COX‑2 is an enzyme normally present in very low amounts, but it ramps up significantly when the body perceives damage or inflammation. Inflammatory signaling molecules (such as IL‑1β and TNF‑α) activate gene expression for COX‑2, causing the cells to start producing large amounts of prostaglandins. These prostaglandins contribute to pain, swelling, and increased sensitivity in the tissue. Therefore, COX‑2 is a key target for NSAIDs and COX‑2 inhibitors – they specifically block this inflammation-driven prostaglandin production

The production ramps up in response to:

inflammation
tissue damage
infection

Produces prostaglandins that cause:

pain
fever
inflammation

How NSAIDs provide pain relief

By inhibiting COX-2, the following are reduced:

PGE₂ → less pain and inflammation
PGI₂ → less vasodilation and edema

How NSAIDs cause side effects

By inhibiting COX-1, the following are reduced:

PGE₂ in the stomach lining → increased risk of ulcer
PGI₂ in the kidneys → reduced renal blood flow
TXA₂ in platelets → increased bleeding risk

2.2 Clinical effects

NSAIDs cause:

1. Analgesic effect

Rapid pain relief in:

musculoskeletal pain
acute injuries
menstrual pain
postoperative pain (8.7)

2. Anti-inflammatory effect

Reduces:

swelling
redness
heat
stiffness

This makes NSAIDs superior to paracetamol for inflammatory pain. They have weaker effects on neuropathic pain and in central sensitization (8).

3. Antipyretic effect

NSAIDs lower fever by inhibiting COX‑2 in the hypothalamus, thereby reducing the production of prostaglandin E2 (PGE₂). When PGE₂ is reduced, the body's “thermostat” is reset, and heat production and heat retention are suppressed. The result is that body temperature falls through increased heat loss and decreased metabolic heat production.

2.3 Side effects – why NSAIDs can be dangerous

NSAIDs are effective, but have a significant potential for side effects. This is particularly important for you as a doctor, because NSAIDs are often prescribed “automatically”.

Gastrointestinal side effects

dyspepsia
nausea
ulcer
GI bleeding

Epidemiological studies show that naproxen is at the upper end of NSAIDs in terms of risk for GI bleeding. In several large case-control studies and meta-analyses, naproxen has been associated with about a 3–4 times increased risk of upper GI bleeding compared with non-use. This is in line with – or slightly higher than – ibuprofen, and lower than ketoprofen and piroxicam. (1,2).

Risk factors:

age > 65
previous ulcer
concomitant use of corticosteroids
concomitant use of anticoagulants or SSRIs

Kidney side effects

NSAIDs reduce prostaglandins that keep afferent arterioles open.

Result:

reduced GFR
fluid retention
hyperkalemia
acute kidney failure

“Triple whammy” is used to describe the increased risk of acute kidney failure when a patient uses NSAIDs + ACE inhibitors/angiotensin II receptor blockers + diuretics simultaneously. NSAIDs reduce afferent blood flow (prostaglandin inhibition), ACE inhibitors/angiotensin II receptor blockers dilate the efferent arteriole, and diuretics reduce intravascular volume. The combination causes the kidney to lose the ability to maintain glomerular filtration → risk of acute kidney injury.(13)

Cardiovascular side effects

COX‑2 in the vascular endothelium produces prostacyclin (PGI₂). PGI₂ inhibits platelet activation, causes vasodilation, and protects against thrombosis. When COX‑2 is inhibited, PGI₂ levels drop, while thromboxane A₂ (TXA₂) from platelets (COX‑1 driven) continues unaffected. The result is increased platelet activation, vasoconstriction, and a pro-thrombotic environment. In addition, COX‑2 inhibitors can cause salt and fluid retention, increase blood pressure, and stress the endothelium.

COX-2 inhibitors increase the risk of (4,5,10):

heart attack
stroke

Diclofenac is found to have the highest cardiovascular risk among traditional NSAIDs. This is explained by strong COX‑2 inhibition → prostacyclin reduction without corresponding TXA₂ inhibition. Naproxen has the most neutral CV profile among NSAIDs. The explanation is that naproxen provides persistent platelet inhibition (partial COX‑1 effect), which counteracts the risk of thrombosis. Ibuprofen has moderate risk, but can increase heart attack risk at high doses and long-term use.

Pregnancy

NSAIDs can:

inhibit implantation
increase risk of bleeding
inhibit labor contractions
close the ductus arteriosus in the fetus

Therefore contraindicated in the 3rd trimester.

Other side effects

NSAIDs can cause:

bronchospasm (NSAID asthma)
skin reactions (14)

Contraindications, summarized

NSAIDs should be avoided in (12,13,15):

ulcer disease
severe renal failure
heart failure
uncontrolled hypertension
pregnancy (3rd trimester)

2.4 Interactions

NSAIDs have many clinically important interactions:

ACE inhibitors/ angiotensin II receptor blockers
- → reduced renal blood flow
- → risk of acute kidney failure
Thiazides
- → amplify the “triple whammy”
Anticoagulants and SSRIs
- → increased bleeding risk
Corticosteroids
- → increased GI risk
Lithium
- → NSAIDs reduce lithium excretion → toxicity
Methotrexate
- → reduced excretion → toxicity

2.5 Common NSAIDs and dosing

Medication	Equianalgesic daily dose	Half-life	Dosage
Diclofenac	150 mg	1-2 h	3 doses/day
Ibuprofen	2400 mg	2 h	2-4 doses/day
Naproxen	750 mg	12 h	2 doses/day

These three constitute 70% of NSAID use in Norway (from PP).

Diclofenac (10)

50 mg × 2–3
higher cardiovascular risk

Ibuprofen (12)

200–400 mg × 3
max 1200–1600 mg/day

Naproxen (9)

250–500 mg × 2
lower cardiovascular risk than other NSAIDs

2.6 Selective vs. non-selective NSAIDs

COX-2 selective (celecoxib, etoricoxib)

Advantages:

fewer GI side effects

Disadvantages:

increased cardiovascular risk (4,5)

Non-selective (ibuprofen, naproxen, diclofenac)

Non-selective NSAIDs inhibit both COX-1 and COX-2, thus affecting both inflammation pain (COX-2) and normal protective functions such as gastric mucosa, renal perfusion, and platelet function (COX-1). This explains both the effect and the side effect profile.

Advantages:

broad effect
good documentation

Disadvantages:

GI side effects
renal side effects

2.7 Clinical considerations – when should you choose NSAIDs?

NSAIDs are first choice for (6,7):

inflammatory pain
acute musculoskeletal injuries
menstrual pain
postoperative pain (in combination with paracetamol)

NSAIDs in combination with paracetamol (6,7)

better analgesia than each drug alone
lower need for opioids

NSAIDs should be avoided in (9,10,13):

kidney failure
heart failure
ulcer disease
high cardiovascular risk
pregnancy
concurrent use of anticoagulants
elderly with multimorbidity

2.8 Summary

NSAIDs are effective but require clinical judgment. They work by inhibiting COX-1 and COX-2 and reducing prostaglandins that cause inflammation and pain. At the same time, COX-1 inhibition carries a risk of GI bleeding, kidney failure, and bleeding risk.

As a doctor, you must always consider:

indication
the patient's risk profile
interactions
treatment duration

Reference list

Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104(3A):2S–8S.
Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390(10094):613–624.
Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563–7568.
Solomon SD et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071–1080.
McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013;10(2):e1001388.
Moore RA et al. Nonsteroidal anti-inflammatory drugs for acute pain in adults. Cochrane Database Syst Rev. 2015;CD010794.
Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal anti-inflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Clin Pharmacokinet. 2010;49(1):1–9.
Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173.
Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–779.
Schmidt M, Christiansen CF, Mehnert F, Rothman KJ, Sørensen HT. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population-based case-control study. BMJ. 2011;343:d3450.
Strom BL, Berlin JA, Kinman JL, Spitz PW, Hennessy S, Feldman H, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. JAMA. 1996;275(5):376–382.
The Drug Handbook. NSAIDs – monograph.
Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med. 1999;106(5B):13S–24S.
Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. N Engl J Med. 2003;349: 1442–1449.
U.S. Food and Drug Administration (FDA). Drug Safety Communication: FDA strengthens warning that NSAIDs increase risk of heart attack and stroke, including in pregnancy.

Neuropathic pain: overview and treatment strategy

Neuropathic pain is fundamentally different from nociceptive pain. It is not caused by tissue damage in muscles, joints, or organs, but by damage or dysfunction in the nervous system itself. This means that traditional analgesics such as paracetamol and NSAIDs often have little or no effect.

For you as a doctor, it is crucial to be able to:

recognize neuropathic pain
understand the pathophysiology
choose the correct drug group
dose correctly and titrate slowly
manage side effects
know when to refer

This chapter provides a clinical and pharmacological overview of drug treatment for neuropathic pain.

3.1 What is neuropathic pain?

Neuropathic pain is pain caused by damage or disease in the somatosensory nervous system located in:

peripheral nerves
plexus
nerve roots
spinal cord
brainstem
cerebral cortex

This may be caused by:

diabetes (diabetic polyneuropathy)
postherpetic neuralgia
radiculopathy
trigeminal neuralgia
alcoholic neuropathy
chemotherapy-induced neuropathy
multiple sclerosis
spinal cord injury

Neuropathic pain is often chronic, resistant to treatment, and disabling.

3.2 Typical symptoms and clinical findings

Neuropathic pain has characteristic positive and negative symptoms:

Positive symptoms: Means increased or abnormal nerve activity, which gives too many signals.

Typical findings are:

burning pain
electric shocks
tingling
paresthesias
dysesthesias
allodynia (pain from touch that normally does not hurt)
hyperalgesia (excessive pain from painful stimuli)

Negative symptoms: Means loss of normal nerve function – that is, too few signals.

Typical findings are:

reduced sensitivity
numbness
reduced vibration sense
reduced touch sense

Clinical tests

monofilament
vibration (128 Hz tuning fork)
temperature
pinprick
Sensory mapping

Questionnaire: S-LANSS (Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs)

S-LANSS is a self-administered screening tool designed to identify whether a patient's pain has a neuropathic component. The form combines the patient's descriptions of typical neuropathic pain qualities with simple self-tests of sensation (allodynia and hyperalgesia). A total score of ≥12 indicates that neuropathic pain is likely and should be further evaluated in the clinic. S-LANSS does not replace a clinical examination, but provides a quick, structured basis for distinguishing between nociceptive, neuropathic, and mixed types of pain.

S‑LANSS consists of:

1. Symptom questions

– burning pain

– electric shocks

– pins and needles

– temperature sensitivity

– pain from light touch

2. Simple self-tests

– comparison of touch sensitivity between painful and normal areas

– assessment of increased pain from light pressure

3. Scoring

– total score 0–24

– ≥12 indicates neuropathic pain (screening, not diagnosis)https://data.templateroller.com/pdf_docs/2663/26632/2663218/main_the-s-lanss-pain-score.pdf?4f87903ca6a2b6ae1c190e84dbee8581

3.3 Pathophysiology – why does it hurt?

Neuropathic pain is caused by a combination of:

1. Peripheral sensitization

Injured nerves become hyperactive and fire spontaneously.

2. Ectopic activity

Nerves start sending signals without stimuli.

3. Central sensitization

The spinal cord and brain become hypersensitive.

4. Loss of inhibition

GABA and glycine inhibition are reduced.

5. Glial activation

Microglia and astrocytes release cytokines that amplify pain.

This explains why neuropathic pain:

is chronic
is difficult to treat
requires different drugs than nociceptive pain

3.4 Why don't paracetamol and NSAIDs work?

Paracetamol acts centrally, but does not affect:

sodium channels
calcium channels
synaptic plasticity
glial activation

NSAIDs act peripherally and reduce inflammation, but:

neuropathic pain is not caused by inflammation
prostaglandins play a minor role
COX inhibition provides minimal effect

Therefore, other drug groups must be used.

3.5 Drug selection for neuropathic pain

The following medications are relevant:

Tegretol (carbamazepine)
Sarotex (amitriptyline)
Noritren (nortriptyline)
Cymbalta (duloxetine)
Efexor (venlafaxine)
Neurontin (gabapentin)
Lyrica (pregabalin)
Oxycodone
Tramadol
Lidocaine (local treatment)

This aligns with international guidelines (BMJ Best Practice, NICE, EFNS).

3.6 First choice – what does the evidence say?

First choice (equivalent):

Gabapentin
Pregabalin
Duloxetine
Amitriptyline

Second choice:

Venlafaxine
Nortriptyline
Tramadol (short-term)

Third-line:

Oxycodone (only under specialist follow-up)
Lidocaine patch (for localized pain)

Special case:

Carbamazepine is the first choice for trigeminal neuralgia.

3.7 Principles of medicinal treatment

1. Start low, go slow

Neuropathic drugs require slow titration to avoid side effects.

2. Give the treatment time

Full effect may take 4–8 weeks.

3. Combinations can be useful

Example:

TCA + gabapentin
SNRI + pregabalin

4. Avoid opioids

Opioids have poor effect on neuropathic pain and high risk of dependence.

5. Consider non-pharmacological measures

physiotherapy
TENS
psychoeducation
sleep therapy

3.8 When should you refer?

Referral is recommended in:

therapy failure after 2–3 medications
suspicion of serious neurological disease
rapid progression
significant loss of function
severe side effects
need for opioids

Neuropathic pain requires a completely different approach than nociceptive pain. It is caused by damage to the nervous system and is best treated with:

TCA
SNRI
gabapentinoids
local lidocaine

Opioids should be avoided, except in special cases.

Tricyclic antidepressants (TCA) in the treatment of neuropathic pain

Tricyclic antidepressants (TCAs) are among the oldest medications we have for the treatment of neuropathic pain, and they are still among the most effective. They have a broad mechanism of action that affects pain pathways, sleep, mood, and neuronal excitability. This makes them an important tool in the treatment of chronic pain, especially when sleep disturbances and emotional components are present.

This chapter provides you with a review of TCAs, focusing on amitriptyline (Sarotex) and nortriptyline (Noritren), which are the most commonly used in Norwegian clinical practice.

4.1 Mechanism of action – why TCAs work on pain

TCAs act at multiple levels in the nervous system, and this explains why they are so effective for neuropathic pain.

1. Inhibition of reuptake of norepinephrine and serotonin

This is the main mechanism. By increasing the levels of noradrenaline and serotonin in the synaptic cleft, the activity in the descending inhibitory pain pathways from the brainstem to the spinal cord is enhanced.

Noradrenaline → strongest analgesic effect
Serotonin → contributes, but is less important than NA

This is the reason why TCA often works better than pure SSRIs for pain.

2. Blockade of sodium channels

TCAs block voltage-gated sodium channels in peripheral nerves, which:

reduces ectopic activity
stabilizes hyperactive pain fibers
dampens spontaneous firing

This is the same mechanism as local anesthesia, but weaker.

3. NMDA receptor antagonism

This reduces central sensitization, which is an important component in chronic pain.

4. Anticholinergic effects

Provides sedation and sleep improvement, which can be useful for:

fibromyalgia
chronic muscle pain
pain with insomnia

4.2 Clinical indications

TCAs are used for:

diabetic polyneuropathy
postherpetic neuralgia
radiculopathy (limited effect, but can be tried)
fibromyalgia
chronic muscle pain
mixed pain conditions with sleep disturbances
tension headache
migraine prophylaxis

Amitriptyline is often the first choice for neuropathic pain in Norway.

4.3 Amitriptyline (Sarotex)

Amitriptyline is one of the best-documented medications for neuropathic pain.

Dosage

Starting dose: 10 mg in the evening
Increase by 10 mg every 1–2 weeks
Typical maintenance dose: 10–50 mg
Maximum dose for pain: 75 mg (higher is used only for depression)

Why is it given in the evening?

Sedative effect
Improves sleep
Reduces daytime side effects

Advantages

Good effect for pain + sleep difficulties
Cheap
Long clinical experience

Disadvantages

Anticholinergic side effects
Not suitable for elderly in high doses
Can cause QT prolongation

4.4 Nortriptyline (Noritren)

Nortriptyline is the active metabolite of amitriptyline, but has fewer anticholinergic side effects.

Dosage

Starting dose: 10–25 mg in the morning
May have a stimulating effect → avoid evening dosing
Usual dose: 25–75 mg

Advantages

Fewer side effects than amitriptyline
Better tolerance in the elderly
Less sedation

Disadvantages

Less sleep-inducing
May cause heart rhythm disturbances

4.5 Side effects – important to know as a doctor

TCAs have a wide side effect spectrum, mainly due to the blocking of muscarinic, histamine, and adrenergic receptors.

Anticholinergic side effects

dry mouth
constipation
urinary retention
visual disturbances
confusion (especially in elderly)

Cardiovascular side effects

orthostatic hypotension
tachycardia
QT prolongation
arrhythmias

ECG is recommended for:

older
patients with heart disease
doses > 50 mg

Sedation

pronounced with amitriptyline
less with nortriptyline

Weight gain

Common with long-term use.

4.6 Clinical assessments – when should you choose TCA?

TCA is especially useful when:

the pain condition is chronic
sleep is poor
the patient also has anxiety or depression
there is a lot of allodynia or burning pain
gabapentinoids are not tolerated

TCAs should be avoided in:

prostate hyperplasia (urinary retention)
glaucoma
heart disease
old age and risk of falls
dementia

4.7 Comparison: Amitriptyline vs. Nortriptyline

Property	Amitriptyline	Nortriptyline
Sedation	High	Moderate
Anticholinergic side effects	High	Lower
Effect on sleep	Good	Moderate
Effect on pain	Good	Good
Suitable for the elderly	No	Yes (Better)
Dosage	Evening	Morning

4.8 Summary

Tricyclic antidepressants are among the most effective drugs for neuropathic pain. They work through:

increased noradrenaline and serotonin
sodium channel blockade
NMDA inhibition
central modulation of pain pathways

Amitriptyline is best for pain + sleep problems.
Nortriptyline is best for pain + side effect issues.

Gabapentin and pregabalin (gabapentinoids)

Gabapentin and pregabalin are among the most commonly used medications for neuropathic pain. They are often referred to as "gabapentinoids" and hold a central place in both Norwegian and international guidelines. Although they were originally developed as antiepileptics, their primary clinical use today is the treatment of neuropathic pain.

This chapter provides a clinical and pharmacological review of both medications, with an emphasis on mechanisms of action, dosing, side effects, and evidence.

5.1 Mechanism of action – why gabapentinoids work on neuropathic pain

Gabapentin and pregabalin do not act on GABA receptors, despite the name. Instead, they bind to the α2δ subunit of voltage-gated calcium channels in presynaptic neurons. This reduces the release of glutamate, substance P, and norepinephrine (1,2).

This produces several important effects:

1. Reduced calcium influx

→ less release of glutamate, substance P, and norepinephrine
→ reduced synaptic excitability
→ less pain transmission

2. Reduced ectopic activity in damaged nerves

This is central in neuropathic pain, where nerves fire spontaneously.

3. Reduced central sensitization

Gabapentinoids reduce hyperactivity in the dorsal horn of the spinal cord.

4. Anti-inflammatory effects

Recent research shows that gabapentinoids can also:

reduce pro-inflammatory cytokines
increase anti-inflammatory cytokines

5.2 Pregabalin vs. Gabapentin – what does the evidence say?

A large systematic review and meta-analysis (2024) directly compared pregabalin and gabapentin in 14 studies with 3346 patients.(10)

Main findings:

Pregabalin provides stronger pain relief (VAS reduction)
Pregabalin provides faster effect
Pregabalin provides better quality of life (SF-12/SF-36/EQ-5D)
Pregabalin provides more days with low pain
Gabapentin causes more nausea and vomiting
Pregabalin reduces the need for opioids

This does not mean that gabapentin is bad, but that pregabalin is often more potent and more predictable.

5.3 Gabapentin (Neurontin)

Gabapentin is a first choice for peripheral neuropathic pain.

Pharmacokinetics

Non-linear pharmacokinetics: The body's elimination becomes saturated, so small dose increases lead to disproportionately high concentration. Gabapentin has saturated, non-linear absorption via a saturable amino acid transport protein in the intestine. When the dose is increased, bioavailability decreases, and the concentration therefore rises less than expected.
Requires dosing × 3 for even effect

Dosage

Start: 300 mg in the evening
Day 2: 300 mg × 2
Day 3: 300 mg × 3
Further escalation: increase by 300 mg every 2nd–3rd day
Usual dose: 900–1800 mg/day
Maximum dose: 3600 mg/day (4)

Advantages

Good documentation
Safe for long-term use
Can be used for sleep problems

Disadvantages

Slow escalation
Variable bioavailability
More sedation than pregabalin

5.4 Pregabalin (Lyrica)

Pregabalin is a further development of gabapentin with:

linear pharmacokinetics: Dose ↑ → concentration ↑ proportionally. Half-life and clearance are stable. Pregabalin is absorbed via a non-saturable transport mechanism, and bioavailability is stable (≈90%) regardless of dose. Therefore, dose increase gives a proportional increase in plasma concentration and effect.
faster effect
stronger analgesic potency

Dosage

Start: 75 mg × 2
After 3–7 days: 150 mg × 2
Maximum dose: 300 mg × 2 (600 mg/day) (4)

Advantages

Rapid effect
Predictable absorption
Better documented effect than gabapentin

Disadvantages

More weight gain
More edema
Can cause euphoria → potential for abuse

5.5 Side effects – what must you as a doctor know?

Common side effects

dizziness
fatigue
drowsiness
peripheral edema
weight gain
dry mouth
concentration difficulties (5)

Rare but important side effects

euphoria (pregabalin)
abuse potential (especially pregabalin) (7)
respiratory depression when combined with opioids (6)

risk of falls

Elderly are particularly vulnerable.

5.6 Clinical assessments – when do you choose what?

Choose gabapentin when:

the patient is sensitive to side effects
you want slow titration
sleep problems are prominent

Choose pregabalin when:

rapid effect is desired
pain intensity is high
gabapentin has not worked
the patient has a lot of anxiety (pregabalin has an anxiolytic effect) (4,5)

Poor indications for both:

nonspecific back pain
acute pain
headache (8)

5.7 Combination treatment

Gabapentinoids can be combined with:

TCA (amitriptyline, nortriptyline)
SNRI (duloxetine, venlafaxine)
Local lidocaine. Lidocaine is a local anesthetic that blocks voltage-gated sodium channels, thereby preventing nerve conduction in the area where it is applied. Versatis 700 mg (lidocaine patch 5% for neuropathic pain) is available in Norway.

Avoid combination with:

opioids (increased risk of respiratory depression) (6)
benzodiazepines (increased risk of sedation) (5)

5.8 Tapering

Gabapentinoids must be tapered over:

• 1–2 weeks at a low dose

• 2–4 weeks at high doses

For rapid discontinuation can cause:

• anxiety

• sweating

• sleep difficulties • rebound pain (9)

5.9 Summary

Gabapentin and pregabalin are cornerstones in the treatment of neuropathic pain. They act by binding to the α2δ subunit in calcium channels and reducing neuronal excitability. Pregabalin has better documented efficacy and faster onset, whereas gabapentin is a safe and flexible alternative.

Reference list

Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin and gabapentin. Epilepsy Res. 2007;73(2):137–150.
Fink K, Dooley DJ, Meder WP, et al. Inhibition of neuronal Ca²⁺ influx by gabapentin and pregabalin via α2δ‑subunit binding: relationship to analgesic effects. Pain. 2002;99(1–2): 113–121.
Backonja M, Glanzman RL. Gabapentin dosing, pharmacokinetics and safety in neuropathic pain. Clin Ther. 2003;25(1):81–104.
Frampton JE, Foster RH. Pregabalin: in the treatment of neuropathic pain. Drugs. 2005;65(1):111–118.
Moore RA, Wiffen PJ, Derry S, Toelle T, Rice AS. Gabapentin and pregabalin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;CD007938.
Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid‑related death: a population‑based nested case–control study. BMJ. 2017;358:j3266.
Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014;28(6):491–496.
NICE. Neuropathic pain in adults: pharmacological management in non‑specialist settings. Clinical Guideline CG173. National Institute for Health and Care Excellence; 2013.
The Drug Handbook. Gabapentin and Pregabalin – monographs
Mayoral V, Gálvez R, Ferrándiz M, Miguéns-Vázquez X, Cordero-García C, Alcántara-Montero A, Pérez C, Pérez-Páramo M.

Pregabalin vs. gabapentin in the treatment of neuropathic pain: a comprehensive systematic review and meta-analysis of effectiveness and safety.

Frontiers in Pain Research. 2024; Volume 5.

DOI: https://doi.org/10.3389/fpain.2024.1513597

Full text: https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2024.1513597/full

SNRI (duloxetine and venlafaxine)

SNRI preparations (Serotonin and Noradrenaline Reuptake Inhibitors) are one of the most important drug groups for neuropathic pain, especially in diabetic polyneuropathy and fibromyalgia. They work by increasing the levels of serotonin and noradrenaline in the synaptic cleft, which strengthens the descending inhibitory pain pathways in the spinal cord (1,2). This provides clinically relevant pain relief, even in patients without depression.

This chapter provides a review of duloxetine (Cymbalta) and venlafaxine (Efexor Depot), focusing on mechanisms of action, dosing, side effects, and clinical considerations.

6.1 Mechanism of action – why SNRIs work on pain

SNRIs work by inhibiting the reuptake of:

serotonin (5-HT)
noradrenaline (NA)

in monoaminergic synapses in the brain and spinal cord.

Why does this provide pain relief?

The descending pain-inhibiting pathways from the brainstem (nucleus raphe magnus and locus coeruleus) use serotonin and noradrenaline as neurotransmitters (3).

When reuptake is inhibited:

more serotonin and norepinephrine are available
pain-inhibiting signals are reinforced
the dorsal horn's response to nociceptive signals is reduced

This provides a central analgesic effect, which is particularly useful for:

diabetic polyneuropathy
fibromyalgia
chronic muscle pain
mixed pain patterns (4)

6.2 Duloxetine (Cymbalta)

Duloxetine is the SNRI drug that has the best documented effect on neuropathic pain (4,5).

It is approved for:

diabetic polyneuropathy
fibromyalgia
generalized anxiety disorder
depression

Dosage

Starting dose: 60 mg × 1
Can be increased to 120 mg/day if needed
Effect is expected after 1–2 weeks
Full effect after 4–6 weeks (5)

Advantages

Good documentation for neuropathic pain
Faster effect than TCA
Improves anxiety and depression at the same time
No anticholinergic side effects (5)

Disadvantages

Nausea (most common at the start)
Sleep disturbances or fatigue
Increased sweating
Sexual side effects. Duloxetine can cause sexual side effects in both men and women, typically related to increased serotonergic activity. Common side effects are decreased libido, delayed orgasm/ejaculation, anorgasmia (difficulty achieving orgasm), erectile dysfunction (in men). SNRIs generally cause fewer sexual side effects than SSRIs, but more than TCAs and pregabalin/gabapentin. The side effects are dose-dependent and may decrease over time. (6)

When should you choose duloxetine?

for diabetic polyneuropathy
for fibromyalgia
for pain + anxiety/depression
when TCA is not tolerated
when the patient wants daytime medication without sedation (4,5)

6.3 Venlafaxine (Efexor Depot)

Venlafaxine is not formally approved for neuropathic pain, but has good documentation and is often used as a second choice when duloxetine does not work or is not tolerated (7).

Dosage

Starting dose: 75 mg × 1
Increase to 150 mg × 1 after 1–2 weeks
Maximum dose for pain: 225 mg × 1 (7)

Pharmacology

Low dose → primarily serotonergic effect
Higher dose (>150 mg) → strong noradrenergic effect

It is the noradrenergic effect that provides pain relief (8).

Advantages

Good effect in neuropathic pain
Suitable for concurrent depression
Extended-release form provides steady plasma concentration (7)

Disadvantages

Increase in blood pressure (dose-dependent)
Discontinuation syndrome with abrupt stop
Nausea, restlessness, sweating (6,7)

When should you choose venlafaxine?

when duloxetine does not work
when the patient has concurrent depression
when gabapentinoids are not tolerated (4)

6.4 Serotonergic syndrome – important warning

Serotonergic syndrome is a potentially life-threatening condition.

Cause

Combination of serotonergic drugs, e.g.:

SNRI + MAO inhibitor
SNRI + tramadol
SNRI + SSRI
SNRI + linezolid

Symptoms

urinary, confusion
tachycardia
hypertension
hyperreflexia
clonus
fever
diarrhea
tremors (9)

Severe syndrome

high fever
rigidity
seizures
unconsciousness

Treatment

discontinuation of the triggering drug
benzodiazepines
cooling
intensive monitoring in severe cases (9)

6.5 Clinical assessments – when do you choose SNRI?

SNRIs are particularly useful when:

the pain is neuropathic
the patient also has anxiety or depression
TCA is not tolerated
gabapentinoids do not have sufficient effect
the patient wants daytime medication without sedation (4.5)

SNRIs should be avoided in:

uncontrolled hypertension (venlafaxine)
severe liver disease (duloxetine)
concurrent use of MAO inhibitors
high risk of serotonin syndrome (9)

6.6 Summary

SNRIs are an important group of drugs for neuropathic pain. Duloxetine is the first choice for diabetic polyneuropathy and fibromyalgia, while venlafaxine is a good alternative in cases of concurrent depression or when duloxetine does not work. Both work by enhancing descending pain-inhibitory pathways through increased serotonin and norepinephrine.

Reference list

Stahl SM. Mechanisms of antidepressant analgesia: actions in the descending pain pathway. CNS Spectr. 2013;18(6):285–287.
Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66(6):355–474.
Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Do antidepressants have an analgesic effect in psychogenic pain and somatoform pain disorder? A structured evidence‑based review. Pain Med. 2000;1(4):310–316.
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta‑analysis. Lancet Neurol. 2015;14(2):162–173.
Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or fibromyalgia. Cochrane Database Syst Rev. 2014;CD007115.
Baldwin DS, Foong T. Antidepressant drugs and sexual dysfunction: evidence and implications. Int J Clin Pract. 2013;67(11):1132–1140.
Sindrup SH, Jensen TS. Venlafaxine for neuropathic pain: a randomized, double‑blind, placebo‑controlled cross‑over study. Pain. 1999;83(2):163–167.
Blier P. Pharmacology of venlafaxine. J Clin Psychopharmacol. 1994;14(3 Suppl 1):14S–18S.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–1120.

Opioids

Opioids are among the most potent pain-relieving medications we have, but at the same time among the most demanding to use correctly. They can provide very good relief for acute severe pain and cancer-related pain, but have limited benefit for long-term non-malignant pain. The risk of dependence, tolerance development, respiratory depression, and cognitive effects means that prescribing requires careful consideration.

This chapter provides a clinically useful overview of:

mechanisms of action
differences between various opioids
pharmacokinetics
tolerance and dependence
equianalgesic doses
opioid rotation
clinical assessments
driving license regulations

7.1 Mechanism of action – how opioids work

Opioids exert their effect by binding to opioid receptors in both the central nervous system and the peripheral nervous system (1,2,3).

The main receptors are:

μ-receptor (MOP) – primarily responsible for analgesia
δ-receptor
κ-receptor

Activation of the μ-receptor causes:

pain relief
euphoria
respiratory depression
constipation
sedation
development of dependence
pupil constriction

Cellular mechanism of action

When the μ-receptor is stimulated:

opens potassium channels → the neuron hyperpolarizes → reduced excitability
calcium channels are inhibited → less release of glutamate, substance P and other transmitters

The result is reduced transmission of nociceptive signals both in the spinal cord and brain.

7.2 Pharmacological differences between opioids

Although all opioids act via the μ-receptor, they vary considerably in potency, metabolism and side effect profile (4).

Morphine

is considered the reference drug
forms an active metabolite (M6G) that can accumulate in kidney failure
can cause histamine release → itching and blood pressure drop

Oxycodone

1.3–2 times as potent as morphine
less histamine release
good bioavailability
available both as depot and fast-acting

Tramadol

weak opioid
additionally, it inhibits reuptake of serotonin and noradrenaline
increases risk of serotonergic syndrome
lower potential for dependence than strong opioids

Codeine

prodrug that is converted to morphine via CYP2D6
large individual variation in metabolism
5–10% are ultra-rapid metabolizers → risk of toxicity
10% are "poor metabolizers" → poor effect

Buprenorphine

partial agonist, meaning that the substance activates the receptor, but not fully – even if it binds 100%. It therefore gives a submaximal effect compared to a full agonist (such as morphine).
ZEQ has a ceiling effect on respiratory depression (safer than full agonist)
lower dependence potential, but can displace other opioids from the receptor (high affinity). Can therefore trigger withdrawal in patients on full agonist.
often used as a patch (Norspan) for chronic pain

7.3 Clinical indications for opioids

Good indications

acute severe pain
postoperative pain
cancer pain
palliative care (5)
kidney stone (short-term)
acute fractures

Poor indications

chronic non-malignant pain
fibromyalgia
headache
unspecified back pain (6)
neuropathic pain (weak effect)

Combination of opioid with other medications

Opioids + benzodiazepines, increase the risk of:

respiratory depression
overdose
death (10)

Opioids + gabapentinoids increase the risk of:

sedation
respiratory depression
falls (12)

Opioids + alcohol

Opioids + alcohol = greatly increased risk of respiratory depression, sedation, and overdose, because both depress the central nervous system and enhance each other's effect (8).

Tapering

Tapering should be done gradually to reduce withdrawal symptoms.

General principles:

reduction 5–10% per week with long-term use
slower with high doses
Consider support with non-opioid analgesics (13)

Common withdrawal symptoms:

restlessness
sweating
abdominal pain
diarrhea
sleep disturbances (13)

7.4 Tolerance, dependence, and opioid-induced hyperalgesia

Tolerance

With repeated use, the body adapts to the opioid, and higher doses are required for the same effect.

Dependence and development of tolerance

Opioids activate the brain's reward system via dopamine, which carries the risk of:

tolerance
dependence
misuse
withdrawal (3,8)

The risk increases with:

high dose
long-term use
combination with benzodiazepines or gabapentinoids (10)

Opioid-induced hyperalgesia

Prolonged use can paradoxically increase pain sensitivity.

Mechanisms include:

NMDA activation
glial activation
increased glutamate activity

This is an important reason why opioids are rarely suitable for chronic pain.

7.5 Side effects

Common side effects

nausea
constipation (all patients should receive laxatives)
sedation
itching
urinary retention (7)

Serious side effects

respiratory depression
QT prolongation (especially methadone)
delirium
falls in the elderly

7.6 Tramadol – weak opioid

Tramadol has two mechanisms of action:

μ-receptor agonism
inhibition of serotonin and noradrenaline reuptake

Dosage

capsules: 50 mg × 3
depot: 75–200 mg × 1–2

Risk

serotonergic syndrome
seizures
interactions with antidepressants

7.7 Oxycodone – strong opioid

Depot (OxyContin)

starting dose: 5 mg × 2
runtime: approx. 12 hours

Fast-acting (OxyNorm)

5 mg every 6 hours
runtime: approx. 6 hours

7.8 Buprenorphine (Norspan) – pain patch

Properties

partial agonist
less respiratory depression
less euphoria
lower potential for dependence

Dosage

start: 5 µg/hour
change weekly
maximum effect after 72 hours

7.9 Codeine/Paracetamol (Paralgin Forte)

Codeine

approximately 10% is converted to morphine
max codeine dose: 90 mg/day

Paracetamol

max 3 g/day

Effect

duration of action: 4–6 hours
maximum effect after 1–2 hours

7.10 Summary

Opioids are effective for acute and cancer-related pain, but have:

high risk of dependence
significant side effects
limited effect for long-term non-malignant pain

They should be used targeted, short-term, and with a clear follow-up plan.

Reference list

Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133–S153.
Fields HL. State-dependent opioid control of pain. Annu Rev Neurosci. 2004;27:1–27.
Volkow ND, McLellan AT. Opioid abuse in chronic pain — misconceptions and mitigation strategies. N Engl J Med. 2016;374(13):1253–1263.
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.
World Health Organization (WHO). Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. Geneva: WHO; 1996.
Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain. Ann Intern Med. 2015;162(4):276–286.
Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347–1354.
Centers for Disease Control and Prevention (CDC). CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016.
Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104(3):570–587.
Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics. BMJ. 2015;350:h2698.
McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. 2nd ed. American Society of Health-System Pharmacists; 2018.
Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case–control study. BMJ. 2017;358:j3266.
Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations. JAMA. 2015;314(19):2032–2033.

Equianalgesic doses and opioid conversion

How to calculate, switch, and dose opioids safely in clinical practice. Equianalgesic doses are the foundation for safe and correct use of opioids. They are used whenever one:

switches from one opioid to another
changes the route of administration (e.g., from intravenous to oral)
considers total opioid load
calculates morphine equivalents for driving license assessment
assesses risk of respiratory depression
plans tapering

This chapter provides a complete, clinically applicable review of how to calculate and use equianalgesic doses in practice.

8.1 What does “equianalgesic dose” mean?

An equianalgesic dose is defined as:

The amount of an opioid that provides the same pain relief as 30 mg of oral morphine.

30 mg morphine p.o. is the reference point in all tables and is used as the standard in both Norwegian and international guidelines.

All other opioids are measured against this reference.

8.2 Why do we need equianalgesic doses?

Opioids vary significantly in:

potency
bioavailability
metabolism
half-life
receptor affinity
active metabolites

This means that equal doses do not produce the same effect. Equianalgesic doses are used to:

compare the strength of different opioids
assess switching between opioids
reduce the risk during rotation
understand dose‑response relationships (1)

These are not treatment recommendations, but pharmacological ratios that show relative strength.

Examples of switching:

20 mg oxycodone p.o. ≈ 30 mg morphine p.o.
150 mg tramadol p.o. ≈ 30 mg morphine p.o.
200 mg codeine p.o. ≈ 30 mg morphine p.o.

Equianalgesic tables are indicative when it comes to dosing – individual differences in drug effect are large (1,2)

Reduce the dose when switching – often 25–50% reduction due to incomplete cross-tolerance [2]

Assess kidney function, age, and comorbidity
Avoid concurrent sedatives
Monitor the patient closely during the first 24–72 hours (3)

Factors that affect equianalgesic ratios

genetics (CYP2D6, CYP3A4)
age
kidney and liver function
tolerance
concurrent use of other medications
pain intensity and type (2,3)

8.3 Equianalgesic table (oral doses)

Based on the Drug Handbook and other sources (1,4-9)

Medication	Relative strength (morphine/substance)	Dose equivalent to 30 mg morphine p.o.
Morphine	1	30 mg
Oxycodone	1,3 – 2	approx. 20 mg
Codeine	0,05 – 0,15	approx. 200 mg
Tramadol	0,1 – 0,2	approximately 150 mg
Buprenorphine (patch)	–	approx. 15 µg/hour
Hydromorphone	4 – 7	4–7 mg
Methadone	very variable	2–10 mg (specialist only)

Important: Hydromorphone (Palladon) is a strong opioid analgesic, a semi-synthetic derivative of morphine, with 4–7 times stronger analgesic effect than morphine per mg. Methadone has unpredictable pharmacokinetics and should only be handled by experienced clinicians.

8.4 Principles for Opioid Rotation (Conversion)

This is one of the most critical areas in pain management.

Step 1: Calculate the total daily dose of the old opioid

Include:

scheduled doses
as-needed doses
both long-acting and immediate-release

Step 2: Find the equianalgesic dose of the new opioid

Use the table above.

Step 3: Reduce the calculated dose due to incomplete cross-tolerance

This is crucial for patient safety.

Common opioids: reduce by 25–50 %
Methadone: reduce by 75–90 %

Step 4: Divide the daily dose into appropriate single doses

Depends on:

depot vs. immediate-release
half-life
clinical situation

Step 5: Titrate according to effect and side effects

Frequent assessment is necessary, especially during the first day.

8.5 Why must we reduce the dose when switching opioids?

Because tolerance to one opioid not does not give full tolerance to another.

Causes:

different receptor affinity
different metabolism
different distribution
different active metabolites

This is called incomplete cross-tolerance, and is one of the most common causes of overdose in case of incorrect switching.

8.6 Clinical examples

Example 1: Paralgin Forte → Tramadol

Paralgin Forte 2 × 4 = 8 tablets/day
1 tablet = 30 mg codeine
→ total codeine dose = 240 mg/day

Equianalgesic relationship:
150 mg tramadol ≈ 200 mg codeine → ratio = 0.75

Calculation:
240 mg codeine × 0.75 = 180 mg tramadol/day

Reduction 25%:
180 × 0.75 = 135 mg/day

Suggestion:
Tramadol depot 100 mg × 1 + 50 mg as needed

Example 2: Tramadol → Buprenorphine patch

Tramadol 50 mg × 3 = 150 mg/day

150 mg tramadol ≈ 30 mg morphine

Buprenorphine patch 15 µg/hour ≈ 30 mg morphine/day

Reduction 25% → still closest to 10–15 µg/hour patch

Example 3: Oxycodone → Morphine

Oxycodone 10 mg × 2 = 20 mg/day

20 mg oxycodone ≈ 30 mg morphine

Reduction 25% → approx. 22–23 mg morphine/day

Example 4: Morphine → Oxycodone

Morphine 60 mg/day

60 mg morphine × 0.66 ≈ 40 mg oxycodone

Reduction 25% → approx. 30 mg oxycodone/day

8.7 Common errors in opioid conversion

These are typical errors in clinical practice:

forgets rescue doses
forgets to reduce dose when switching
starts too high
switches to methadone without a specialist
combines multiple opioids unnecessarily
uses fast-acting as regular medication
forgets laxatives

8.8 Clinical assessments – when should you switch opioid?

Good reasons

troublesome side effects
insufficient effect
kidney failure (avoid morphine)
need for patches (compliance)
need for sustained-release preparations

Poor reasons

“the patient wants something stronger”
“the patient has heard that oxycodone is better”
“the patient does not want morphine”

8.9 Summary

Equianalgesic doses are absolutely central for safe opioid use.

Key points:

30 mg morphine p.o. is the reference
use tables, not guessing
reduce the dose by 25–50% when switching
methadone requires specialist
buprenorphine patches 15 μg/hour ≈ 30 mg morphine/day
always consider the indication and risk

Reference list

McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists; 2018.
Fine PG, Portenoy RK. Establishing “best practices” for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage. 2009;38(3):418–425.
Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long‑term opioid therapy for chronic pain. Ann Intern Med. 2015;162(4):276–286.
Mercadante S. Oxycodone versus morphine in cancer pain: a systematic review. J Clin Oncol. 2011;29(5): 289–294.
Quigley C. Hydromorphone for acute and chronic pain. J Pain Symptom Manage. 2004;28(5):497–504.
Fallon M, Laird B, Shaw C, et al. Fentanyl transdermal system for cancer pain. Lancet Oncol. 2008;9(5): 757–765.
Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. Drug Alcohol Depend. 2005;70(2 Suppl):S13–S21.
Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolites in ultra‑rapid metabolizers due to CYP2D6 duplication. Clin Pharmacol Ther. 2007;82(1):41–47.
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.

Driver's license and opioids

Opioids affect responsiveness, attention, judgment, and motor skills. Therefore, there are strict rules for when patients using opioids may drive a car (1-4). As a doctor, you have both a medical and a legal responsibility to assess whether the patient meets the health requirements in the driving license regulations (3-5).

This chapter provides a complete and clinically applicable overview of:

applicable regulations
assessment of driving ability
dose limits
combination rules
reporting obligation
practical examples

9.1 The regulations – what does the regulation say?

Assessment of driving licenses and opioids is based on two main sources:

The Norwegian Directorate of Health's guide for addictive medicines (1)
The driving license regulation, Chapter 14 (substances that may affect driving ability) (3)

These documents form the basis for all medical assessments related to driving and opioid use (1-5).

9.2 Driving license group 1 (passenger car, moped, motorcycle)

This is the only group where regular use of opioids can can be compatible with a driver's license — but only under strict conditions (1-3).

The health requirements are met when:

The opioid is used regularly for more than 7 days
– the patient must be stable on the dose
– no dose changes in the last week
There is a clear medical indication
– acute pain does not qualify
– chronic pain must be well documented
The medication is long-acting
– depot preparations (Dolcontin, OxyContin)
– buprenorphine patches
– fast-acting opioids are considered short-acting (see exceptions below)
Total daily dose is under 300 mg morphine equivalents
– all opioids must be converted to morphine equivalents
– see Chapter 8 for conversion
The patient does not have side effects that affect driving ability (6-9)
– sedation
– dizziness
– cognitive impairment
– slowed reaction time

9.3 Fast-acting opioids – when are they considered 'long-acting'?

An important exception in the regulations (1,3):

If a fast-acting opioid is taken regularly at least three times daily, it can be considered long-acting.

Examples:

Paralgin Forte 1 × 3 regularly → can be considered long-acting
OxyNorm 5 mg × 3 regularly → can be considered as long-acting

But:

as needed medication
irregular use
varying doses

→ meets not the health requirements.

9.4 Driver's license group 2 and 3 (bus, truck, emergency)

Here the regulations are absolute (3-5):

Regular use of opioids is incompatible with the health requirements.

This applies regardless:

dose
preparation
indication
stability

Patients in these groups cannot use opioids regularly.

9.5 Short-term use of opioids (< 7 days)

Short-term use of opioids (< 7 days) usually does not result in a driving ban, but the patient cannot drive until they know how the medication affects them, and not if they are sedated, dizzy, or cognitively impaired.

In acute conditions (postoperative pain, acute back pain, fracture):

the patient should not drive a car (1,3)
this applies to all opioids
applies all day

Now that the effect of the medication is known and the patient uses a single dose, the patient should wait:

at least 8 hours before driving
16 hours for long-acting preparations (1)

This must be clearly communicated (5).

9.9 Clinical examples

Example 1: OxyContin 10 mg × 2

total oxycodone dose = 20 mg/day
corresponds to approx. 30 mg of morphine
under 300 mg
→ health requirements met if stable dose and no side effects

Example 2: Tramadol 50 mg × 3

considered long-acting (regular × 3)
150 mg tramadol ≈ 30 mg morphine
→ health requirements met if stable dose

Example 3: OxyNorm 5 mg × 3 as needed

not regular
→ health requirements not met

9.10 Summary

Assessment of driver's licenses and opioids is a complex but critical area. As a doctor, you must:

know the regulations
assess the patient's function
calculate morphine equivalents
document the assessment
inform the patient clearly

This is both a medical and legal responsibility.

Reference list

The Norwegian Directorate of Health. Addictive medications – prescribing and appropriateness. Oslo: Norwegian Directorate of Health; latest edition.
The Norwegian Directorate of Health. Health requirements for driving licenses – guide to the driving license regulations. Oslo: Norwegian Directorate of Health; latest edition.
Regulation on driving licenses, etc. (the driving license regulations). Chapter 14: Substances that may affect driving ability.
Norwegian Public Roads Administration. Health requirements for driving licenses – practical guidance for healthcare personnel.
The Norwegian Directorate of Health. Guide on duty to report and duty to provide information for healthcare personnel.
Bramness JG, Skurtveit S, Mørland J. Clinical impairment of drivers using opioids. Tidsskr Nor Legeforen. 2002;122: 2222–2225.
Mørland J, Waal H. Opioids and traffic safety. Tidsskr Nor Legeforen. 2016;136: 1355–1358.
Verster JC, Volkerts ER. Clinical pharmacology, clinical efficacy, and behavioral toxicity of opioids. Curr Drug Saf. 2005;1(1): 63–82.
Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Impairment from opioid analgesics. Pain Med. 2003;4(4): 372–389.
Chou R et al. The effectiveness and risks of long-term opioid therapy for chronic pain. Ann Intern Med. 2015;162:276–286.
Gomes T et al. Gabapentin, opioids, and the risk of opioid-related death. BMJ. 2017;358:j3266.
Park TW et al. Benzodiazepine prescribing patterns and overdose risk with opioids. BMJ. 2015;350:h2698.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112–1120.
McPherson ML. Demystifying Opioid Conversion Calculations. 2nd ed. ASHP; 2018.
World Health Organization (WHO). Guidelines for the pharmacological treatment of persisting pain in adults with medical illnesses.
European Medicines Agency (EMA). Opioids and driving – safety communication.
Norwegian Directorate of Health & Norwegian Medicines Agency. Interactions and sedation with combination therapy.

Norwegian Public Roads Administration. Duty to report to the County Governor – health requirements and permanent impairment.

Combination of medications and driving ability.

Combination of medications that depress the central nervous system (CNS) is one of the most common causes of reduced driving ability in patients who otherwise function well in daily life (1,3). For you as a physician, this is an area with both medical and legal significance. It requires that you understand how different medications enhance each other's effects, and how this affects the assessment of the health requirements in the driving license regulations (1,2).

This chapter provides an overview of:

which medications affect driving ability
how combinations increase risk
how to assess function and safety
how to calculate the allowed dose when using combinations
what to do when health requirements are not met

10.1 Why are combinations dangerous?

Many medications have a depressant effect on the CNS. When used together, the effect can become:

additive (1 + 1 = 2)
synergistic (1 + 1 = 3 or more)

This applies especially to medicines that affect:

alertness
reaction time
attention
judgment
coordination
cognitive function

Even small doses can cause significant functional impairment when combined (3).

10.2 Which medicines are included in the "risk group"?

The following drug groups have documented effects on the ability to drive:

1. Opioids

morphine
oxycodone
tramadol
codeine
buprenorphine

2. Benzodiazepines

diazepam
oxazepam
alprazolam
clonazepam

3. Z-hypnotics

zolpidem
zopiclone

4. Sedating antihistamines

promethazine
hydroxyzine

5. Antipsychotics

quetiapine
olanzapine
haloperidol

6. Antiepileptics

gabapentin
pregabalin
carbamazepine

7. Antidepressants

TCA (amitriptyline, nortriptyline)
SNRI (duloxetine, venlafaxine)
some SSRIs (lower risk, but not zero)

All of these can affect driving ability — and combinations increase the risk (3).

10.3 Two such medications → halving of the allowed daily dose

When the patient uses two medications that affect the CNS, the allowed maximum daily dose of both drugs is halved (1,3,10-12).

This applies to combinations of:

opioids
benzodiazepines
z-hypnotics
sedating antihistamines
antipsychotics
antiepileptic drugs
antidepressants (especially TCAs and SNRIs) (9)

Example:

Oxycodone 20 mg/day + pregabalin 300 mg/day
→ both are sedating
→ allowed dose for both must be halved (1.12)

10.4 Three or more such medicinal products → health requirements not met

This is an absolute rule:

The use of three or more sedative medications means that the health requirements are not met (1,3,10).

This applies even if:

the doses are low
the patient feels "used to it"
the patient believes they drive safely

The regulation is very clear about this.

10.5 Clinical assessments – what must you do as a doctor?

1. Map all medications the patient uses

Include (1,5):

regular medications
as needed medication
over-the-counter preparations
natural remedies

2. Assess whether the medications affect driving ability

This is a medical assessment (1,7-9)

3. Calculate morphine equivalents

See chapter 8.3 (11)

4. Assess combinations

two sedative medications → halving (1, 10-12)
three or more → health requirement not met

5. Document the assessment in the medical record

This is a legal requirement (5).

6. Clearly inform the patient

The patient is obliged to not drive if in doubt (1,5).

7. Report to the County Governor in case of permanent impairment

When a patient does not meet the health requirements for a driver's license, and the impairment is assumed to last more than 6 months, the doctor is obliged to send a report to the County Governor. The report should be brief, factual, medically justified, and without unnecessary health information. This follows from the reporting obligation in the Health Personnel Act § 34 (5).

Drafting the report to the County Governor (Reporting Obligation Regulations §§ 2–3)

The message must be in writing.
It must include identification of the patient.
It must state which health requirement is not met.
It must state the reason for the failure (short medical justification).
It must state that the failure is expected to last > 6 months.
It must not include more health information than necessary.
As a general rule, the patient must be informed about the message.

10.6 Clinical examples

Example 1: Oxycodone + pregabalin

two sedative drugs
→ allowed dose halved
→ health requirements met if within halved limit

Example 2: Tramadol + amitriptyline

two sedative drugs
→ allowed dose halved
→ NOTE: risk of serotonergic syndrome

Example 3: Oxycodone + pregabalin + quetiapine

three sedative drugs
→ health requirements not met

Example 4: Zopiclone in the evening + fixed oxycodone

two sedative drugs
→ allowed dose halved
→ NOTE: z-hypnotics have a hangover effect

Example 5: Pregabalin + duloxetine

two sedative drugs
→ allowed dose halved
→ common combination for neuropathic pain
→ requires careful assessment of driving ability

10.7 Summary

Combination of drugs that affect the CNS is one of the main causes of reduced driving ability.

As a doctor, you must:

know which drugs affect driving ability
assess combinations carefully
halve the permitted daily dose for two such medications
reject health requirements for three or more
document the assessment
inform the patient clearly

This is both a medical and legal responsibility.

Reference list

Norwegian Directorate of Health. Substances that can affect driving ability (§§ 35–37). The Driver's License Guide
Regulation on driving licenses etc. Chapter 14 – Substances that can affect driving ability
NHI.no. Driving and addictive medications