Pain types:
1. Nociceptive Pain. Acute, ❌ and physiological. Somatic (skin, bone, joint, muscle.) pain = ❌, localised. Visceral (large intestine, pancreas.) referred or ❌.

2. Neuropathic (pathologic) pain. ❌ from noxious stimuli. Chronic, ❌ damage.
• Related pain syndromes: ❌ neuropathy, post-herpetic, IBS
• Reported pain is ❌ than physical exam findings.

3. Inflammatory. More acute. ❌, pathological.

4. ❌ pain. Chronic. No neuronal damage, noxious stimuli, or inflammation.

Molecular mechanisms of pain:

1. Transduction
Stimulation of ❌. Uses afferent fibres. ❌ activation threshold eg >45C or <5C. Sensitisation by bradykinin, ❌ serotonin, can ❌ threshold.

2. Transmission
Conduction of impulse from periphery to ❌ across ❌ horn of spinal cord. Neurotransmitters: ❌ Associated with thalamus and sensorimotor cortex.

3. Perception
Afferent impulse goes to ❌ pathways; also associated with thalamus and cortex. ❌ experience: cognition, behaviour

4. Modulation
❌ transduction, conduction, transmission. Local inhibitory neurons: ❌. Descending pathway is ❌, also affected by the inhibitory substances: ❌, 5HT, NA, endogenous cannabinoids.

The analgesic ladder (WHO)"
STEP 1 ❌ e.g. paracetamol, NSAIDs
STEP 2 ❌ suitable for moderate pain (or ❌) ± simple analgesics e.g. codeine, dihydrocodeine
STEP 3 Opioid suitable for ❌ pain ± simple analgesics e.g. morphine

Endogenous opioids: ❌ at opioid receptors, eg Beta endorphin, Enkephalin
• Receptors: pre/post ❌ terminals in the ❌ cord, limbic system, PNS
• Inhibit ❌ - stimulate inhibitory pathways
• Euphoria

All opioid Rs are coupled to ❌. R activation has many ❌ consequences.

Opioid Analgesics: Buprenorphine, codeine, fentanyl, morphine, diamorphine (heroin), oxycodone, tramadol.
• Agonists at ❌ opioid Rs.

❌ stimulation (raphe magnus)
• Less activity in ❌ neurons = descending 5-HT neurons (brainstem)
• Presynaptic connection = ❌ nociceptive neurons (spinal cord)

Inhibition of GABA permits ❌ firing in ❌ pathway.
Analgesia: inhibition of release of ❌ (substance P, NO, glutamate.)

Opioid analgesia:
Muse R activation = increased pain ❌
Kappa R activation = ❌ m-mediated analgesia + has unopposed ❌ analgesia

Also present on peripheral nerves:
Muse agonists: decrease ❌ of nociceptive neurons (inflamed tissue)
Kappa receptors: endothelial cells, T lymphocytes, macrophages. Modulate ❌ response.

All opioids have maximum potency for ❌ receptors.
Morphine, diamorphine, pethidine, oxycodone, codeine have specificity for ❌.
Methadone has ❌ kappa or delta specificity, ❌ muse.
Fentanyl has no ❌ sensitivity, just muse and ❌.
Naloxone has specificity for muse, less for kappa(but ❌ than most opiods), and some for delta.

Other CNS effects:
- Euphoria - Mediated by ❌, contributes to analgesia
- Dysphorial (❌)
- Respiratory Depression - primary cause of ❌; depress rhythm generation in ❌, desensitize brainstem ❌ (increasing ❌)
- Cough suppression - Antitussive, direct effect on ❌ in medulla - ❌

Peripheral effects:
GI Tract
• increased ❌ tone (m, k)
• ❌ (80%)
• affecst ❌ of other drugs
• less stomach ❌ – anorexia, N&V

Cardiovascular system
• Few effects on heart or circulation
• High dose – depress ❌ center
• Hypotension (parenteral use of ❌)

SEs are dose dependent.

Tolerance and dependence:
❌ use causes adaptive changes in R function.
• More drug for same effects = ❌
• ❌= adverse physiological effects (dependence)

Tolerance
• Learned (❌)
• (Adaptive) ❌
• Most pharmacological effects (❌ constipation, pupil constriction)

Dependence (withdrawal syndrome, m)
• Anxiety, sweating, craving (12h)
• Rhinorrhea, ❌ pupils, yawning, chills, pilo❌, ❌ventilation, diarrhoea
• Duration of action varies

Cautions and contraindications:
Caution
• Impaired ❌ function (sleep apnea, asthma, COPD?)
• Renal impairment (dose ❌)?
• Pregnancy?
Contraindications:
• Raised ❌
• Acute head injury (❌)

Tx options:
- Oral ❌ generally first-line strong opioid. Active metabolites (from ❌ impairment) lead to opioid toxicity = excessive ❌, confusion, restlessness, hallucinations

- Oral ❌ is second-line. Risk of toxicity with renal impairment. ❌ inhibitors.

- ❌ safer option for patients with GFR < 30 mL/min