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Jörn Schneede

of Analgesic MedicationsClinical Pharmacology

Läkemedelscentrum

Contents of this Lecture

Clinical Pharmacology of:• Paracetamol (Acetaminophen)• Non-steroidal anti-inflammatory drugs (NSAIDS) / COX-2

specific inhibitors• Opioids•Warning against codeine

• Analgesics in renal and hepatic failure• Pain in premature children

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Clinical Pharmacology includes

• Mechanism of Action • Absorption/Distribution/Metabolism/ Elimination (ADME)• Indication for use / dosage• Adverse effects• Any special precautions that should be taken

• Contraindications• Pregnancy and breast-feeding• Infants/elderly/disabled• Interactions• Health economics, cost-utility, cost-effectiveness

ParacetamolAcetaminophen

Non Steroidal Anti-inflammatory Drugs

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Paracetamol

Paracetamol • Paracetamol has been in use for more

than a century• It has both analgesic and antipyretic action• Still, the exact mechanism of its action is unclear:

• Prostaglandin-synthesis (POX)

• COX-2• COX-3 (in dogs)• Descending serotinergic

pathways• PG-E2 inhibition in CNS• Cannabinoid system• NO-inhibitor (spinal cord)

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Absorption / Elimination

• It is available as tablets (adults), suspension or syrup for children and suppositories

• On oral administration it is absorbed from the intestine (70%), stomach and colon (30%)

• The rate of absorption is rapid and depends on the dose

• The time taken to reach maximum plasma concentration (Tmax) is 15 - 30 minutes depends on the preparation (“Zapp”, “Novum”)

• Tmax is 2 - 3 hours with suppositories• Bioavailability ranges from 60-90%

Elimination (mainly renal in conjugated forms)• Paracetamol is metabolized in the liver, mainly phase II reactions• Only 2 - 5% is excreted unchanged in urine

Metabolism / Elimination

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Indications and dosages

• It is used as an analgesic drug for mild to moderate pain– E.g. tooth ache / teething pain in children, back pain, joint and

muscle pain, headache, dysmenorrhoea• Relief of fever in adults and children

Dosage• Adults – Up to 1g oral / rectal, every 6 hours

• 4 g should not be exceeded / day

• Children – Oral / rectal 20 mg / kg – every 6 hours• 125 mg/ kg should not be exceeded

Side effects

• Paracetamol is normally well tolerated and has only few side effects at therapeutic doses

• It has good haematological tolerability and does not alter haemostasis / platelet function

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Caution

• Since it is metabolized in the liver it must be used with caution / or omitted in the presence of liver impairment• Max. dose 3 g/d• Do not use for prolonged time

• In patients with renal impairment, the dose of paracetamol should be reduced

• Do not exceed 4g/day in adults and 125 mg/ kg in children

Adverse effectsHepatotoxicity with an overdose of paracetamol

• This can occur when a patient does not get adequate relief with paracetamol and decides to take more than the prescribed dose of a maximum of 4g/day

• Or uses OTC-paracetamol in addition to Citodon

• Intentional overdose is the leading cause of acute liver failure in the US, UK and Australia

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Adverse Effects

• N-acetylcysteine (NAC) is the antidote for paracetamol poisoning and it is most effective when administered within 8 - 10 hours after ingestion

• Renal toxicity • Overdose can cause severe

kidney necrosis

Metabolism of acetaminophen (top center) to hepatotoxic metabolites. (GSH, glutathione; SG, glutathione moiety).

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Ändring av 200 µg/ml gränsen i 1976

Avvikelsesrapport

• Underläkare medicin, Skellefteå kontaktar mig som kemlab-jour. • Under perioden 16 09 14 – 16 09 21 har vi rapporterat svängande S-

paracetamol mellan 9 och 22 µmol/L i prov från denna patient. • Acetylcysteinbehandling inneliggande under denna tid på grund av

påvisbart S-paracetamol. • Underläkaren uppfattar att patienten är leversjuk. • Enligt giftinformationscentralens anvisning ska

acetylcysteinbehandling pågå tills att S-paracetamol ej längre kan påvisas.

• Underläkaren har varit i kontakt med giftinformationscentralen som ställt sig frågande till de svängande S-paracetamolkoncentrationerna

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Bilirubin interferes – ultrafiltration of sample

Adverse Effects

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Paracetamol and ASD

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Review and metaanalysis

Relatively vague concepts

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It is not decided yet

NSAIDsNon Steroidal Anti-inflammatory Drugs

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History of Aspirin

• Salicylate from the bark of the willow tree and was used to treat fever and rheumatism for centuries

• In the late 19th century, salicylic acid and later acetylsalicylic acid was synthesized and called aspirin.

• Aspirin was widely used to treat fever, pain, cardiovascular disease

• Reye syndrome in children after viral infection• Replaced by paracetamol in the 80s

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

• They are diverse group of compounds which were later synthesized, with actions similar to that of aspirin and became known as NSAIDs

• The mechanism of action of aspirin / NSAIDs (COX-inhibition) was discovered in the 1960’s by Prof Vane, who was awarded a Nobel prize in Medicine in 1982

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Non-steroidal Anti-inflammatory Drugs -NSAIDs

• NSAIDs are widely used to treat pain and inflammation

• They act through inhibition of the two isoforms of the enzyme cyclooxygenase (COX) – i.e. COX-1 and COX-2

• NSAIDs that act on both the enzymes are known as non-selective NSAIDs (ns-NSAIDs)

• NSAIDs which act predominantly on the COX-2 enzyme are known as specific COX-2 inhibitors (also referred to as Coxibs)

The Two Isoforms of COX

• COX-1 is a normal constituent in the body for homeostasis, such as in:• Gastric mucosa – gastric cytoprotection• Kidney – Sodium and water balance / renal perfusion• Platelets – for aggregation

• COX-2 is induced in the presence of injury, inflammation and neoplastic disease

• COX-2 is also a normal constituent in the many organs such as: Kidney, brain, endothelium, ovary and uterus

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What happens when there is tissue injury?

Membrane phospholipidsCell wallinjury

Releases

Arachidonic Acid

Phospholipase A2

COX-1 & COX-2 that is induced with injury and inflammation, cancer

PGH2 (Prostaglandin H2)

PGD2 TXA2PGE2PGI2 PGF2

Prostaglandins- PGE2 as the most significant Thromboxane

Phospholipid from cell membrane

Arachidonic Acid

PGH2 5-HPETE

Leukotrienes

LipoxygenaseCyclo-oxygenase

ProstaglandinsThromboxane

These inflammatory mediators activate the nociceptors on the Aδ and c fibres and result in pain and sensitization

Arachidonic Acid Cascade

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NSAIDs / COX-2 inhibitors

Reduced Prostaglandins and Thromboxane, resulting in reduced pain

Phospholipid from cell membrane

Arachidonic Acid

PGH2 5-HPETE

Leukotrienes

LipoxygenaseCyclo-oxygenase

ProstaglandinsThromboxane

Arachidonic Acid Cascade

Increased risk of asthma

ns-NSAIDs

Acetylsalicylic acid (aspirin)• Tablet, suppository

Ibuprofen• Tablet, suspension for children

• Faster onset of action

• Inhibits platelet effects of ASA

Naproxen• Tablet

• Longer effect times

Diclofenac• Tablet, suppositories, parenteral forms

available

• Possibly highest CVD-risk among ns-NSAIDs

Celecoxib (Celebra)• Oral capsules

Etoricoxib (Arcoxia)• Tablets

Parecoxib (Dynastat) • Parenteral

COX-2 specific inhibitors (= Coxibs)

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Absorption and Elimination

• When administered orally, aspirin, ns-NSAIDs and Coxibs are well absorbed and reach therapeutic levels within 30 to 60 minutes.

Indications

• Both the ns-NSAIDs and Coxibs have the same efficacy in postoperative analgesia• Sole analgesia for day-surgery • Along with opioids for major surgery

• Musculo-skeletal pain – e.g. back pain, joints, muscle sprains etc.• Osteoarthritis• Rheumatoid arthritis

• Not indicated for neuropathic pain

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Side effects / Adverse effects

Gastrointestinal effects•The risk of erosions, ulcers and bleeding is higher with ns-NSAIDs compared to Coxibs.

•Risk is greater • In elderly patients• Those who are also taking aspirin

•Risk can be reduced by adding a proton-pump inhibitor (e.g. omeprazole) to ns-NSAIDs.

• H2 receptor blockers are not very effective.

Renal effects

• Both COX-1 & 2 are constituent enzymes in the kidney• Maintain renal perfusion and sodium/water balance

• Both ns-NSAIDs and Coxibs can cause• Hypertension, edema• Counteract anti-hypertensive treatment• Decrease GFR that may be significant in patients with

impaired renal function or transient hypotension / hypovolaemia in the postoperative period

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PG

↑PG

NSAIDS ↓PG

AII

↑AII

ACEi/ARB ↓AII

Normal

↓volume

↓volumewith ACEi + NSAID

Afferent Glomerulus Efferent

Cardiovascular effects

• Coxibs: large intervention studies for primary prophylaxis of CRC and Mb Alzheimer

• Some studies have shown that there was a higher risk of thrombotic cardiovascular events (stroke, heart attack) when on Coxibs when compared to ns-NSAIDs such as naproxen

• Other studies have shown that the cardiovascular events are similar, but possibly highest for etoricoxib and diclofenac

• Current recommendations are that Coxibs should not be used in patients with active cardiovascular disease and a known thrombotic condition

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Summary

• Both drugs are effective in providing pain relief for moderate pain

• The mechanism of action of both groups of drugs is by inhibiting the COX-2 enzyme that is induced with injury, inflammation and cancer

• Gastrointestinal side effects are less with coxibs

NS-NSAIDs / Coxibs

Summary (cont.)

• Coxibs have no effect on platelet aggregation• Both NS-NSAIDs / Coxibs should be used with caution in

patients with renal impairment and in the elderly• Coxibs should not be used in patients with active

cardiovascular disease or known thrombotic risks• Coxibs can be given to patients with aspirin

sensitive asthma• Both drugs should be used for the shortest period of time at

the lowest effective dosage

NS-NSAIDs / Coxibs

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Opioids

Opioids

• Opium alkaloids derived from the opium poppy has been used for pain relief for centuries

• Morphine was isolated by Sertuner in 1813• The glass syringe was introduced in 1844• Since then morphine has been the mainstay in the

management of severe pain• The term “opioid” is referred to any drug, either natural, semi-

synthetic or fully synthetic, which has actions similar to morphine

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Chemical structure

Available Opioids

• Opioids on the WHO essential drug list• Morphine• Codeine• Tramadol

Natural• Morphine• Codeine

Semi-Synthetic• Hydromorphone• Oxycodone• Diacetylmorphine

(heroin) • Naloxone

(antagonist)

Fully Synthetic• Pethidine

(meperidine)• Tramadol• Methadone• Fentanyl• Alfentanil• Sufentanil• Remifentanil

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Chemical structure

Opioids can be classified as:

• Strong opioids used for severe pain– Morphine, Oxycodone, Pethidine, Fentanyl

• Weak Opioids used for moderate pain– Codeine, Tramadol

Tapentadol

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Weak opioids

The analgesic ladder for acute pain management

Strong opioids

Mechanism of Action

• Opioids act by binding to opioid receptors (complex proteins embedded within the cell membrane of neurons)

Opioid receptors are found in the brain and in the dorsal horn of the spinal cord

There are three different opioid receptors - µ, δ, κ

µ - most relevant as all clinically used opioids exert their action via the µ -opioid receptor

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Opioid receptor types

Mechanism of Action

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Cellular Actions

• Opioids bind to opioid receptors • G-protein coupled receptors

• Closing voltage-gated Ca2+ channels on presynaptic nerve terminals• Inhibit release of• Glutamate, acetylcholine, norepinephrine,

serotonin, and substance P• Hyperpolarizing and thus inhibiting postsynaptic neurons

by opening K+ channels• Inhibition of pain signals/pain perception

Morphine (strong opioid)

• Is the most widely used opioid for the control of severe pain

• It can be given by all large number of different routes

• It is well absorbed when given orally and has a bioavailability of around 30-35%.

• High extraction drug – bioavailability increases dramatically in liver failure / shunting

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Oral morphine

Immediate release morphine (e.g. Morfin Meda)• Aqueous / liquid morphine (usually prepared

as 1-2 mg / ml) • Tablet morphine (10 mg)• Need to be given every four hours for continuous relief of

severe painSustained Release (SR) Morphine Tablets (e.g. Dolcontin)• Morphine is released slowly over 12 hours • 10 mg, 30 mg, 60 mg• These tablets are given twice a day

Parenteral morphine (10 mg / I ml ampoule)

Intramuscular / subcutaneous morphine• Onset of Analgesia 15 - 20 min • Peak action 45 - 90 min• Duration of action 4 hours

Intravenous route is chosen when rapid control of severe pain is desired.

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Metabolism

The principle pathway of metabolism is conjugation with glucuronic acid in hepatic and extra-hepatic (kidney) sites • Morphine-3 and morphine-6 glucuronides that are excreted

mainly by the kidneys• Morphine-6-glucuronide is biologically active and more potent

than morphine itself• Morphine should be used with caution in patients with hepatic

and renal impairment

Codeine phosphate – “Weak” opioid

• Oral tablet 15mg; 30 mg

• Is well absorbed and there is no first pass metabolism

in the liver

• Codeine is metabolized to morphine (CYP2D6); which accounts for

its analgesic effect

• 60 mg of codeine has an equi-analgesic effect compared with

650 mg aspirin

• Has an anti-tussive effect and is often used in cough mixtures

• Is widely used in fixed combination with paracetamol• Cause minimal sedation, nausea, vomiting and constipation

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Metabolic pathways of codeine biotransformationN Engl J Med 2004;351:2827-31

Metabolic pathways of codeine biotransformationN Engl J Med 2004;351:2827-31

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2006

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2012

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2013

FDAApril 20th 2017

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ACOG Practice Advisory on Codeine and Tramadol for Breastfeeding Women, April 2017

• 1) Consider prescribing an opioid analgesic other than codeine or tramadol.

• According to the American Academy of Pediatrics Committee on Drugs, butorphanol, morphine, or hydromorphone are preferred agents for breastfeeding mothers requiring narcotics for pain control. Morphine and hydromorphone can be dosed via oral or IV route.

• 2) If a codeine-containing medication is considered the preferred choice, the risks and benefits of this drug and the reasoning behind the FDA warning should be discussed with each family.

FDA January 2018 Labeling Changes

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Tramadol – Weak opioid

• This is also known as an “atypical opioid”• It has a dual mechanism of action:

• weak opioid receptor binding properties• Inhibits the re-uptake of serotonin and noradrenaline at the

descending inhibitory pathway• This may become a problem when discontinuing the drug

• It is available • Oral capsule (50 mg)• Injection – 50 mg / ml – in 2 ml ampoules

Tramadol

• It is well absorbed when given orally• Time to effect is around 30 minutes and can last

5 - 6 hours• Sedation is minimal• Can cause nausea, vomiting, dizziness• Abuse potential is low • Is used as a weak opioid, however as it has a dual mechanism

of action – its analgesic efficacy is superior to codeine –Maximum daily dose is 400 mg

• Not for treatment of chronic pain / neuropathic pain

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Metabolism

• Tramadol is metabolized by the liver (CYP2D6 as codeine) and excreted by the kidneys

• Tramadol has an active metabolite (O-desmethyltramadol) – that is also excreted by the kidney

• The daily dose should be reduced in the presence of chronic renal failure

• Usefulness in chronic pain is debated

Läkemedelsverkets senaste rekommendation

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Opioid related side effects

• On initiation of opioid therapy, patients frequently report acute side effects of sedation, dizziness, nausea and vomiting

• After a few days these symptoms subside except for constipation

• This is noted in patients with cancer pain• (Constipation prophylaxis is very important)

Opioids and Tolerance Patients can develop tolerance when opioids are used for an extended period • E.g. cancer pain; intensive care unitsTolerance is defined as reduction of the pharmacological effect of an opioid:• When the same dose produces a lesser effect• Increasing doses of drug are required to produce the same effect • The mechanisms of the development of tolerance are complexOpioid-induced hyperalgesia (OIH)• a phenomenon observed in patients treated with opioids, who paradoxically

demonstrate an increased sensitivity to painful stimuli. • associated with hyperalgesia, allodynia, or both• often different quality/location than the original pain• N-methyl-D-aspartate receptor activation may have a central role•

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Physical Dependence and Addiction

Physical dependence is a state of adaptation by the body with extended use of an opioid • It is manifested by withdrawal symptoms with abrupt cessation

of the opioid, rapid dose reduction or administration of an opioid antagonist

Addiction to opioids is drug seeking behavior where the person is looking for opioids for its euphoric action rather than pain relief alone

Analgesics in liver and renal disease

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NSAID och cirrhos

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Analgesics in hepatic and renal failureLiver disease/cirrhosis Renal failure

Paracetamol Up to 3 g GFR >10-20: normal dose

NSAID Avoid AvoidMorphine Use with caution AvoidCodeine Avoid Avoid or reduce doseTramadol Avoid Avoid in severe renal

failureOxycodone Use with caution Great caution in severe

renal failureBuprenorfin Can be used, but dose

adjustments necessaryOK. No dose-adjustment

for transdermal prep.Remifentanil Can be used OKFentanyl Can be used, but monitor OKMethadone Not adviced OK, red. dose GFR < 10

Acute pain relief in premature infants

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Pain in premature• Vegetative reactions to pain already seen from post-

gestational week 22• Lower liver enzyme activity –• slower elimination of opioids• longer effect times

• BBB not fully developed – more CNS exposure to opioids• More risk of respiratory depression, bradycardia,

hypotension• Relative distribution of μ, δ and κ- receptors is not fully

developed• Relative to body weight higher doses needed for

anesthesia

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Pain in premature (cont.)• Differential development of opioid receptors in time in

different areas of the pain system• Faster development of receptors in pons and medulla

oblongata region• Increased risk of respiratory depression,

bradycardia and rigidity• Despite all theses factors:• Opioids are useful as analgesics in premature children• Dose adjustments should primarily be based on

clinical effects and not mainly on adjustments according to body weight