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OPIOIDS - Pharmacology

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Opioids

Transmitters: Endogenous opioid peptides Enkephalins (m & d receptors)

Dynorphins (κ receptors)

Endorphins

Actions Opioids stimulate axons of inhibitory

interneurons

Peripheral inflammation: Sensitivity to opioids in spinal cord is increased

Peripheral neuropathic pain: Sensitivity to opioids is greatly reduced

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Pain Modulation: Central mechanisms

Gate control Aβ axons stimulate inhibitory interneuron Activity in central projection neuron is reduced

Opiate-induced analgesia μ Receptor :Agonists: Morphine; Antagonist: CTAP Reduces acute pain & hyperalgesia in most models δ Receptor :Agonist: SNC80 , Antagonist: Naltrindole Reduces acute pain & hyperalgesia in inflam. pain

models May have fewer side effects (Constipation, respiratory

depression, physical dependence) than μ-agonists κ Receptor : Agonist: U50,488 No effect on chronic muscle pain Locations: PAGM, Ventral medulla, Dorsal horn

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SG

Lamina I

C-fibre GlutamateLamina VsP

PAG, RVM etc

Descendingpathways

Ca2+

VDCCs

BRAIN

Dorsal Horn

Carbamazapine,lignocaine

GABAPENTIN

amytriptyline

Ketamine

OPIOIDS

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CodeineCodeineWeak opioidsWeak opioids

Weak Weak agonist, methbolize to morphine agonist, methbolize to morphine (30%)(30%)

Dose 30-60 mg oral q 4-6 hrs Dose 30-60 mg oral q 4-6 hrs

Side effects : constipation/ itching/ nausea/ Side effects : constipation/ itching/ nausea/ vomitingvomiting

Available as:Available as:

TWC(15)TWC(15)

TWC(30)TWC(30)

Codeine (15, 30 mg)Codeine (15, 30 mg)

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TramadolTramadol

Weak opioids (cont.)Weak opioids (cont.)

Weak Weak µµ agonist agonist

Amine uptake inhibiting actionAmine uptake inhibiting action:NE and serotonin:NE and serotonin

Dose 50-100 mg oral q 6 hrsDose 50-100 mg oral q 6 hrs

Anticholinergic side effects: tachycardia, Anticholinergic side effects: tachycardia, nausea, vomiting,voiding difficulty, sweatingnausea, vomiting,voiding difficulty, sweating

Available as IR, ER (Tramal) and combinationAvailable as IR, ER (Tramal) and combination ( ( Ultracet® (Tramadol& paracetamol) Ultracet® (Tramadol& paracetamol)

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Strong Opioids Strong Opioids

agonists: agonists: morphine, pethidine,fentanylmorphine, pethidine,fentanyl,,

methadonemethadone

partial agonists :-partial agonists :-buprenorphine,buprenorphine,

pentazocinepentazocine

agonist-antagonist :- agonist-antagonist :- nalbuphinenalbuphine

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Morphine Pethidine

Bioavailability: 30-60%, due to1st part metabolism

Immediate release: 3-4 hr Extended release:12-24 h Metabolize to M6G

(agonist), M3G (neurotoxicity), may accumulate in renal failure

Only parenteral route in TH Faster onset, short duration (2-3

hr) No more effective than morphine

at treating biliary or renal pain High addictive potential (rush and

stimulant effect) More CNS toxicity (i.e. seizures,

delirium due to nor-pethidine metabolite

Should not be used any more

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MST, MS Contin (10, 30, 60 mg)

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Kapanol (20, 50, 100 mg)

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Immediate release opioid

Oral morphine solution

Rama, Siriraj, Songkhla 2mg/ml

-stability, convenience, dosage

Fentanyl lollipop Fentanyl buccal tablet

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Methadone Cheap and available for opioid maintenance Racemic of L and R –isoform, theoretically support NMDA

and mu-receptor mechanism Variable half life, extended with long term use Use as third line, for switching in refractory case Start at lower dose, then slowly titrate Study recommends to switch from morphine to methadone in

3-day (one third reduction and substitution with equianalgesic dose (4 to 1- 6 to 1 ratio), followed by a one week titration

Fredheim OM, Eur J Pain. 2007 ;11:599-604.

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Narcotic Type 2

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Fentanyl TTS ( Durogesic®/ D-Trans® )•12, 25, 50, 100 µgm/patch•onset : 6-12 hrs, change patch q 3 days•Should not use for acute pain due to delay onset•Indications

Terminal cancer pts. who are not able to eatCancer of the head and neck regionPts. who develop severe side effects of oral

narcoticsPts. who consume very high dose oral narcotics

Transdermal narcoticsTransdermal narcotics

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Opioid Therapy and Chemical Dependency

• Risk of addiction: Evolving viewAcute pain: Very unlikelyCancer pain: Very unlikelyChronic noncancer pain:

Surveys of patients without abuse or psychopathology show rare addiction

Surveys that include patients with abuse or psychopathology show mixed results

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Opioid Therapy: Drug Selection

• Immediate-release preparations Used mainly

For acute pain

For dose finding during initial treatment of chronic pain

For “rescue” dosing

Can be used for long-term management in select patients

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Opioid Therapy: Drug Selection

Immediate-release preparationsCombination products

Acetaminophen, aspirin, or ibuprofen combined with codeine, hydrocodone, dihydrocodeine

Single-entity drugs, eg, morphine

Tramadol

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Opioid Therapy: Drug Selection

Extended-release preparations Preferred because of improved treatment

adherence and the likelihood of reduced risk in those with addictive disease

Morphine, oxycodone, fentanyl, hydromorphone, codeine, tramadol, buprenorphine Adjust dose q 2–3 d

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Opioid Therapy: Drug Selection

Role of methadoneAnother useful long-acting drug

Unique pharmacology when commercially available as the racemic mixture

Potency greater than expected based on single-dose studies

When used for pain: multiple daily doses, steady-state in 1 to several weeks

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Opioid Selection:Poor Choices for Chronic Pain

MeperidinePoor absorption and toxic metabolite

Propoxyphene Poor efficacy and toxic metabolite

Mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, dezocine)Compete with agonists withdrawal

Analgesic ceiling effect

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Opioid Therapy: Routes of Administration

Oral and transdermal—preferred Oral transmucosal—available for fentanyl

and used for breakthrough pain Rectal route—limited use Parenteral—SQ and IV preferred and feasible

for long-term therapy Intraspinal—intrathecal generally preferred for

long-term use

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Opioid Therapy: Guidelines

Consider use of a long-acting drug and a “rescue” drug—usually 5%–15% of the total daily dose

Baseline dose increases: 25%–100% orequal to “rescue” dose use

Increase “rescue” dose as baseline dose increases

Treat side effects

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Opioid Therapy: Side Effects

CommonConstipation

Somnolence, mental clouding

Less common Nausea – Sweating Myoclonus – Amenorrhea Itch – Sexual dysfunction Urinary retention – Headache

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Opioid Responsiveness

• Opioid dose titration over time is critical to successful opioid therapy

• Goal: Increase dose until pain relief is adequate or intolerable and unmanageable side effects occur

• No maximal or “correct” dose• Responsiveness of an individual patient to a

specific drug cannot be determined unless dose was increased to treatment-limiting toxicity

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Poor Opioid Responsiveness

If dose escalation adverse effects Better side-effect management Pharmacologic strategy to lower opioid

requirementSpinal route of administrationAdd nonopioid or adjuvant analgesic

“Opioid rotation” Nonpharmacologic strategy to lower opioid

requirement

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Opioid Rotation

Based on large intraindividual variation in response to different opioids

Reduce equianalgesic dose by 25%–50% with provisos: Reduce less if pain severe Reduce more if medically frail Reduce less if same drug by different route Reduce fentanyl less Reduce methadone more: 75%–90%

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Equianalgesic Table

PO/PR (mg) Analgesic SC/IV/IM (mg)

30 Morphine 10

4–8 Hydromorphone 1.5

20 Oxycodone -

20 Methadone 10

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Acknowledgement

Assoc. Professor Chutamanee Suttisisang Assoc. Professor Pongparadee Chaudakestrin Assist. Professor Penkae Ketuman Professor Anthony Dickenson