What do we know about tramadol?

Mr. Novák, suffering from chronic pain due to grade III osteoarthritis of the left hip joint, is visiting your pain management clinic for the first time.

He was referred by his general practitioner, who prescribed a fixed combination of tramadol/paracetamol 75 mg/650 mg, 1 tablet as needed, up to 3 times a day.
The patient takes all three doses, yet the treatment is not sufficiently effective. In addition to the tramadol/paracetamol combination, he is chronically using aceclofenac 100 mg, 1-0-1 and tramadol SR 100 mg, 1-0-1.

Let's focus on the tramadol/paracetamol combination, specifically on the active substance tramadol, which is the most commonly prescribed opioid in Czechia.

What is the pharmacodynamic profile of tramadol?
Would it be possible to increase its dosage (currently 425 mg/day) in order to enhance its analgesic effect?

Help

It is a partial agonist of μ receptors and an antagonist of δ receptors.
Increasing the dose does not make sense due to the ceiling effect.

It is a μ-opioid receptor agonist that also inhibits the reuptake of serotonin and norepinephrine.
Increasing the dose does not make sense due to the ceiling effect.

It is a partial agonist of μ receptors and an antagonist of δ receptors.
The dose can be increased without the risk of reaching a ceiling effect.

It is a μ-opioid receptor agonist that also inhibits the reuptake of serotonin and norepinephrine.
The dose can be increased without the risk of reaching a ceiling effect.

years

185

man

Examination

Personal history
Coxarthrosis l. sin.
Hypertension
Hypercholesterolemia
Anemia
Benign prostatic hyperplasia
Chronic kidney disease (CKD G3a)

Pharmacological history
aceclofenac 100 mg 1-0-1
tramadol SR 100 mg 1-0-1
tramadol/paracetamol 75 mg/650 mg 1-1-1
perindopril/amlodipine 4 mg/10 mg 1-0-0
simvastatin 20 mg 0-0-1
ferrous sulfate 247.25 mg 0-1-0
tamsulosin 0.4 mg 1-0-0

Help

CKD G3a – Chronic Kidney Disease category based on eGFR, where CKD G3a corresponds to 45-59 ml/min/1.73m²;

SR – sustained-release, usually a tablet form of the medication with prolonged release of the active ingredient, most commonly over 12 hours, therefore dosed twice daily (for some medications even 24 hours, according to the SPC). Can also be labeled as extended-release (ER);

paracetamol – in some countries better known as acetaminophen;

5-HT – 5-Hydroxytryptamine – a precursor to serotonin, commonly referred to as serotonin;

NE – Norepinephrine;

Intrinsic activity – The ability of a ligand to activate a signaling cascade and induce a pharmacological effect (it takes values between 0 and 1);

Affinity – The tendency of a ligand to bind to a specific receptor;

Agonist – A substance that binds to a receptor (has affinity) and induces a biological response (has intrinsic activity), mimicking the response of an endogenous ligand;

Partial agonist – An agonist that leads to less than maximum effects (intrinsic activity > 0 and < 1);

Antagonist – A substance that binds to a receptor but DOES NOT induce a biological response, i.e., it has no intrinsic activity (intrinsic activity = 0);

Displacement – Refers to a situation where one drug/ligand occupies a binding site on a receptor or plasma protein, thereby preventing another drug/ligand from binding and influencing its effect;