CSB464 2021 Pain Part 3 (PDF)

CSB464: NEUROLOGY PAIN AND ANALGESIA (PART 3) PHARMACOLOGY OF ANALGESICS Tony Hall FSHP  COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of th...

CSB464: NEUROLOGY PAIN AND ANALGESIA (PART 3) PHARMACOLOGY OF ANALGESICS Tony Hall FSHP  COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of the Queensland University of Technology persuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice 3 Analgesic Interventions  Pharmacological  systemic  local  Surgical  Acupuncture/ dry needling  TENS  Physiotherapy  RF Systemic analgesic interventions World Health Organisation Pain Ladder  Step 1 of the ladder is for mild pain. Non-opioid analgesics such as paracetamol or NSAIDs are used +/-adjuvant agents Step 2 is employed for persisting or worsening pain. A weak opioid such as codeine or tramadol is added to step 1 Step 3 is for severe pain. Strong opioid analgesia replaces step 2. The dose is titrated according to response  There is no evidence supporting the application of the ‘Pain Ladder’  It was invented to promote use of analgesic medicines in Palliative Care internationally  There is no such thing as a ‘weak’ opioid although we might now refer to ‘atypical’ opioids Simple analgesics - Paracetamol or acetaminophen (USP)  No clear explanation of how paracetamol works  Suggested (?)  Inhibits cyclooxygenase enzyme (COX-3) within brain  A metabolite of NAPQI mimics anandamide, the natural ligand for the CB-1 receptor  Toxicity  Low level of adverse effects – very well tolerated except if daily dose > 3-4g Paracetamol (continued)  Metabolised by glucuronidation, sulphation and oxidation by CYP1A2 to NAPQI (N-acetyl-p- benzoquinone imine)which this then detoxified by glutathione  Glutathione stores a limited and saturated at doses > 6-7g/day (150mg/kg in paediatrics)  NAPQI is very hepatotoxic and renal and liver damage is often fatal when doses of ~10g paracetamol are taken Paracetamol (continued)  Paracetamol not a very potent analgesic but is amongst the safest analgesic as long as dose restricted to a maximum of 4g/day  Available OTC almost anywhere in small quantities  Larger quantities only on prescription or purchased from a pharmacy  Now often available in combination with other analgesics e.g. NSAIDs, opioids and caffeine to improve(?) analgesic efficacy Simple analgesics - NSAIDs  NSAIDs are inhibitors of cyclooxygenase enzymes  COX isoenzymes: COX-1 and COX-2  COX-1 is a constitutive enzyme involved in maintaining renal perfusion and mucin production on stomach lining  COX-2 is an inducible enzyme involved in the inflammatory process and platelet aggregation (prostacyclin and thromboxane)  NSAIDs can be COX-2 selective = ‘coxibs’ or non-selective (COX-1 and COX-2)  ‘Coxibs’ often lose their COX- selectivity as dose increases  NSAIDs work by reducing the production of inflammatory mediators (prostaglandins) but may cause peptic ulceration, renal impairment, and increase risks of heart failure, AMI and CVA NSAIDs (some not available in Australia)  Salicylates  Anthranilic acid derivatives  Aspirin, diflunisal, salsalate  Mefenamic acid  Proprionic acid derivatives  Sulfonanilides  Ibuprofen, naproxen, fenoprofen,  Nimesulide (hepatotoxic) ketoprofen, flurbiprofen  Acetic acid derivatives  Coxibs ( COX-2 selective)  Indometacin,sulindac, tolmetin, etodolac,  Celecoxib, parecoxib, etoricoxib, ketorolac, diclofenac, nabumetone, aceclofenac  rofecoxib was withdrawn from market  Enolic acid derivatives NB Most NSAIDS are chiral molecules where d-  Piroxicam, meloxicam, tenoxicam, form is active. The exception is diclofenac phenylbutazole Simple analgesics-NSAIDs and Coxibs  Four NSAIDs available OTC  Ibuprofen (e.g. Nurofen®)  Diclofenac (e.g. Voltaren®)  Naproxen (e.g. Naprosyn®)  Mefenamic acid (e.g. Ponstan®)  All Coxibs are prescription only  Little difference between products except in terms of  Route e.g diclofenac topical gel  Onset of action – faster absorption e.g. rapid onset ibuprofen, SR naproxen  CR NSAIDs available on prescription  Of little benefit in chronic pain and now 3rd line choice in inflammatory autoimmune diseases such as Rheumatoid Arthritis Combination Paracetamol + NSAID  Paracetamol + Ibuprofen combinations  Maxigesic® - ibuprofen 150mg + paracetamol 500mg ◼ Recommended dose – 1-2 tablets every six hours (Max EIGHT tablets daily)  Nuramol® + Mersynofen® - ibuprofen 200mg + paracetamol 500mg ◼ Recommended dose- 1 tablet every eight hours  Paracetamol MR (Panadol Osteo®)  Paracetamol 665mg SR ◼ Recommended dose – 2 tablets every eight hours (= 4g/day) Opioids  All opioids work by mimicking the natural ligands for the opioid receptors in brain and spinal cord: endorphin and enkephalin  A number of different opioid receptors have been described: Mu (m) , Kappa (k), Delta (d)  Analgesia associated mainly with m receptor Opioids  Now divided into typical and atypical opioids  Typical opioids:  morphine, codeine, oxycodone, fentanyl, alfentanil, sufentanil, hydromorphone, pethidine,  Atypical opioids:  buprenorphine, tramadol, tapentadol, methadone Opioids  All opioids are reasonably potent  NNT for 50% reduction in pain ~2  But:  Tolerance develops reasonably quickly reducing analgesic efficacy  Dependence (and Addiction in some individuals)  Long term use associated with Opioid-induced Hyperalgesia and Endocrine Disorders Routes of administration  Oral  Parenteral  Topical e.g. transdermal  Sublingual  Intranasal  Neuroaxial  Intraspinal ◼ Epidural, ◼ Intrathecal  Intraventricular Dose forms  Oral opioid analgesics usually available as  Immediate release ◼ analgesic effect for short period of time e.g. 2-4 hours e.g. oxycodone IR (Endone®)  Modified or Controlled Release ◼ for 12 hours e.g. oxycodone CR, ◼ for 24 hours e.g. hydromorphone (Jurnista®) Opioid adverse effects  Sedation  Tolerance sets in quickly so sedation not usually associated with long term use  Constipation  All opioids will effect the enteric nervous system around GIT; slowing GI transit time, allowing water absorption and causing constipation  Constipation is not defined by frequency  Nausea  Opioids inhibit gastric emptying rate  Pruritus  Morphine causes degranulation of mast cells; releasing histamine and causing itching (pruritis) ◼ Highest prevalence after neuro-axial (e.g. epidural) and parenteral administration Adjuvant analgesics - TCAs  Tricyclic antidepressants were the first generation of antidepressants used before introduction of SSRIs and NSRIs  Little used in depression today because of toxicity:  Anticholinergic and Noradrenergic/Serotoninergic Reuptake inhibition  AEs = sedation, dry mouth, blurred vision, constipation, weight gain, orthostatic hypotension, cardiac arrhythmias including T-wave inversion, gynaecomastia in males,  Very low doses still used in pain management to help pain-related sleep disturbance  Amitriptyline 5-25mg each evening  Nortriptyline 5-25mg each evening  Dothiepin 25mg each evening NB avoid taking at night – may cause ‘Hang-over’-like side effects  No evidence of a dose response relationship in pain so little benefit in exceeding 50mg daily  Most effective in nociplastic nerve pain and where sleep depletion Adjuvant analgesics - AEDs  Carbamazepine & Oxcarbazepine  Valproate  Gabapentiniods  Gabapentin & Pregabalin  Gabapentinoids and AEs ineffective in Nociplastic pain (Enke 2018)  Lamotrigine  Topiramate  Major use in nerve related pain  Carbamazepine used in Trigeminal Neuralgia  Gabapentinoids used in peripheral neuropathy e.g. in diabetes and post herpetic neuralgia, ineffective(??  Lamotrigine used in central (post stroke) pain  Topiramate used in migraine prophylaxis  Valproate little used – little evidence of activity AED toxicity  Cause of significant adverse effects  Drowsiness  Dysequilibrium (increased falls risk)  Weight gain (except topiramate)  Cognitive dysfunction e.g. ‘word-finding’  Suicidal ideation (SUDEP ?)  Convulsions Adjuncts in Neuropathic pain Medication Indication NNT (>50% NNH NNH benefit) Minor major Amitriptyline Neuropathic (nociplastic?) pain (Sindrup 2005) 2.0 – 3.0 Neuropathic (nociplastic?) pain (Saata 2006) 2.0 4.4 16 Tricyclic Diabetic neuropathy (Gupta Antidepressants 2004) 3.5 2.7 17 Anti-Epileptic Drugs Diabetic neuropathy (AEDs) (Gupta 2004) 2.7 2.7 Carbamazepine Trigeminal neuralgia (McQuay 1995) 2.6 3.4 Gabapentin Diabetic neuropathy (Backonja 1998) 4 5.0 – 6.0 Neuropathic pain >18 yrs (Rowbotham 1998) 3.2 3.7 Refractory neuropathic pain (Dolin 2004) 3.2 - 3.8 Pregabalin PHN and DPN (Straube 2008) Dose dependent 150mg 7.3 - 150 withdrawal for 300mg 4.4 - 9.5 somnolence (~23%) and 600mg dizziness (~30%) 3.2 - 4.7 Phenytoin Diabetic neuropathy 2.5 3.1 Adjuvant analgesics - Others  Ketamine  Clonidine  Muscle relaxants  BZPs  Baclofen  Dantrolene  Triptans  Ergot derivatives