ON7 Pain Management - Opioid Drugs

Pain types: 1. Nociceptive Pain. Acute, [blank_start]protective[blank_end] and physiological. Somatic (skin, bone, joint, muscle.) pain = [blank_start]throbbing[blank_end], localised. Visceral (large intestine, pancreas.) referred or [blank_start]localised[blank_end]. 2. Neuropathic (pathologic) pain. [blank_start]Disengaged[blank_end] from noxious stimuli. Chronic, [blank_start]neuronal[blank_end] damage. • Related pain syndromes: [blank_start]diabetic[blank_end] neuropathy, post-herpetic, IBS • Reported pain is [blank_start]greater[blank_end] than physical exam findings. 3. Inflammatory. More acute. [blank_start]Repairing[blank_end], pathological. 4. [blank_start]Dysfunctional[blank_end] pain. Chronic. No neuronal damage, noxious stimuli, or inflammation.

Molecular mechanisms of pain: 1. Transduction Stimulation of [blank_start]nociceptors[blank_end]. Uses afferent fibres. [blank_start]High[blank_end] activation threshold eg >45C or <5C. Sensitisation by bradykinin, [blank_start]prostaglandins, interleukins, TNFa,[blank_end] serotonin, can [blank_start]lower[blank_end] threshold. 2. Transmission Conduction of impulse from periphery to [blank_start]CNS[blank_end] across [blank_start]dorsal[blank_end] horn of spinal cord. Neurotransmitters: [blank_start]Glutamate, Substance P, CGRP.[blank_end] Associated with thalamus and sensorimotor cortex. 3. Perception Afferent impulse goes to [blank_start]ascending[blank_end] pathways; also associated with thalamus and cortex. [blank_start]Conscious[blank_end] experience: cognition, behaviour 4. Modulation [blank_start]Suppress[blank_end] transduction, conduction, transmission. Local inhibitory neurons: [blank_start]GABA[blank_end]. Descending pathway is [blank_start]locus coeruleus[blank_end], also affected by the inhibitory substances: [blank_start]Opioids[blank_end], 5HT, NA, endogenous cannabinoids.

The analgesic ladder (WHO)" STEP 1 [blank_start]Non-opioid analgesics[blank_end] e.g. paracetamol, NSAIDs STEP 2 [blank_start]Opioids[blank_end] suitable for moderate pain (or [blank_start]tramadol[blank_end]) ± simple analgesics e.g. codeine, dihydrocodeine STEP 3 Opioid suitable for [blank_start]severe[blank_end] pain ± simple analgesics e.g. morphine

Endogenous opioids: [blank_start]Agonists[blank_end] at opioid receptors, eg Beta endorphin, Enkephalin • Receptors: pre/post [blank_start]synaptic[blank_end] terminals in the [blank_start]apinal[blank_end] cord, limbic system, PNS • Inhibit [blank_start]transmission[blank_end] - stimulate inhibitory pathways • Euphoria All opioid Rs are coupled to [blank_start]inhibitory G proteins[blank_end]. R activation has many [blank_start]intracellular[blank_end] consequences.

Opioid Analgesics: Buprenorphine, codeine, fentanyl, morphine, diamorphine (heroin), oxycodone, tramadol. • Agonists at [blank_start]specific[blank_end] opioid Rs. [blank_start]Muse-R[blank_end] stimulation (raphe magnus) • Less activity in [blank_start]GABA[blank_end] neurons = descending 5-HT neurons (brainstem) • Presynaptic connection = [blank_start]afferent[blank_end] nociceptive neurons (spinal cord) Inhibition of GABA permits [blank_start]increased[blank_end] firing in [blank_start]descending[blank_end] pathway. Analgesia: inhibition of release of [blank_start]pain mediators[blank_end] (substance P, NO, glutamate.)

Opioid analgesia: Muse R activation = increased pain [blank_start]modulation[blank_end] Kappa R activation = [blank_start]antagonizes[blank_end] m-mediated analgesia + has unopposed [blank_start]spinal[blank_end] analgesia Also present on peripheral nerves: Muse agonists: decrease [blank_start]sensitivity[blank_end] of nociceptive neurons (inflamed tissue) Kappa receptors: endothelial cells, T lymphocytes, macrophages. Modulate [blank_start]immune[blank_end] response.

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

Other CNS effects: - Euphoria - Mediated by [blank_start]muse[blank_end], contributes to analgesia - Dysphorial ([blank_start]kappa[blank_end]) - Respiratory Depression - primary cause of [blank_start]morbidity[blank_end]; depress rhythm generation in [blank_start]medulla[blank_end], desensitize brainstem [blank_start]chemoreceptors[blank_end] (increasing [blank_start]pCO2[blank_end]) - Cough suppression - Antitussive, direct effect on [blank_start]cough center[blank_end] in medulla - [blank_start]codeine, dextromethorphan[blank_end]

Peripheral effects: GI Tract • increased [blank_start]resting[blank_end] tone (m, k) • [blank_start]constipation[blank_end] (80%) • affecst [blank_start]absorption[blank_end] of other drugs • less stomach [blank_start]motility[blank_end] – anorexia, N&V Cardiovascular system • Few effects on heart or circulation • High dose – depress [blank_start]medullary vasomotor[blank_end] center • Hypotension (parenteral use of [blank_start]morphine[blank_end]) SEs are dose dependent.

Tolerance and dependence: [blank_start]Continuous[blank_end] use causes adaptive changes in R function. • More drug for same effects = [blank_start]tolerance[blank_end] • [blank_start]Withdrawal[blank_end]= adverse physiological effects (dependence) Tolerance • Learned ([blank_start]psychological[blank_end]) • (Adaptive) [blank_start]R downregulation/desensitization[blank_end] • Most pharmacological effects ([blank_start]not[blank_end] constipation, pupil constriction) Dependence (withdrawal syndrome, m) • Anxiety, sweating, craving (12h) • Rhinorrhea, [blank_start]dilated[blank_end] pupils, yawning, chills, pilo[blank_start]erection[blank_end], [blank_start]hyper[blank_end]ventilation, diarrhoea • Duration of action varies

Cautions and contraindications: Caution • Impaired [blank_start]respiratory[blank_end] function (sleep apnea, asthma, COPD?) • Renal impairment (dose [blank_start]reductions[blank_end])? • Pregnancy? Contraindications: • Raised [blank_start]ICP[blank_end] • Acute head injury ([blank_start]pupillary responses[blank_end])

Strong opioids are used for pain in palliative care.

Tx options: - Oral [blank_start]morphine[blank_end] generally first-line strong opioid. Active metabolites (from [blank_start]renal[blank_end] impairment) lead to opioid toxicity = excessive [blank_start]sedation[blank_end], confusion, restlessness, hallucinations - Oral [blank_start]oxycodone[blank_end] is second-line. Risk of toxicity with renal impairment. [blank_start]CYP[blank_end] inhibitors. - [blank_start]Fentanyl[blank_end] safer option for patients with GFR < 30 mL/min