Pharmacotherapy Eric J. Visser

Lets review the drug cupboard

Paracetamol Does it work? Not sure how paracetamol works? - COX-2, ‘cannabinoid’, serotonin? Mainstay analgesic in most chronic pain protocols Not much good for MSS pain? - exception: older patients? Adverse effects (liver, warfarin; NSAID-like?) Rx for acute LBP - especially as combination drug with NSAID/coxib, tramadol, codeine (NNT 3) Machado GC et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ 2015 Mar 31;350:h1225. doi: 10.1136/bmj.h1225.

Tramadol Good for acute & chronic LBP 1/3rd opioid, 1/3rd SSRI (serotonin), 1/3rd SNRI (nor adrenaline) 1st line for acute & chronic LBP (NNT 4) Effective for neuropathic pain (NNT 4) ↓ Respiratory depression & constipation OK with TCAs, SSRIs, SNRIs; ‘sensible doses’; no seizures Accumulates in renal impairment Pro-drug, 11 active metabolites Won’t work in 10% of patients (like codeine, cytochrome P450 2D6)

Tapentadol SR Like tramadol without the serotonin ‘Weak’ opioid (S8) & NARI in one molecule -noradrenaline is main pain-inhibiting neurotransmitter 2nd line for chronic pain? Effective in nociceptive & neuropathic pain (NNT 4) ↓ Constipation ↓ Side effects than tramadol? Minimal accumulation in renal impairment OK with TCAs, SSRIs, SNRIs Tapentadol SR 50 mg ~ 10 mg oxycodone po ~ 20 mg morphine po

NSAIDs & coxibs Effective (NNT 3) Rapid-acting formulations ARE better Rx acute pain flare-ups (days-fortnight) Do NOT use long-term for chronic pain Renal & gastric risk (NSAIDs) (PPI) Hypertension & cardiovascular risk Naproxen-best cardiovascular risk (MI) Celecoxib-best overall risk profile (gut, bleeding, CVS)

Antidepressants & anticonvulsants TCAs: NOT effective for CLBP Duloxetine (SNRI): moderately effective (noradrenaline effect) - chronic LBP - neuropathic pain (NNT 4) (radicular leg pain?) Gabapentinoids (pregabalin, gabapentin) Not effective for LBP Radicular leg pain?

Opioids don’t work well in CLBP (NNT = 8, NNH = 4) (Level I) Opioids for CLBP? Opioids don’t work well in CLBP (NNT = 8, NNH = 4) (Level I) Adverse effects (tolerance, hyperalgesia, overuse, addiction) Poor risk vs benefit Opioids ‘contraindicated’ in CNSLBP (especially < 60s) Consider in > 60s with spondylosis (more side effects?) Opioid prescribing is always an ongoing therapeutic trial (90 days) 3Ts: tramadol SR, tapentadol SR, transdermal buprenorphine Ceiling dose is ≤ 90 mg oral morphine equivalents/day (no more) Chaparro LE et al. Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. Spine (Phila Pa 1976). 2014 1;39(7):556-63.

Transdermal buprenorphine patch Mu partial agonist, kappa antagonist No ceiling effect for analgesia Use it like any other opioid Safer respiratory profile Safer renal profile (no accumulation) Better dose control....only 1 patch per week

What about Bob? Above the ceiling dose Bob has ‘’opioid non-responsive pain’’ Taper & cease Opioid rotation - tapentadol (wean morphine slowly-may get withdrawal) - oxycodone/naloxone CR - transdermal buprenorphine patch

Radicular (neuropathic) leg pain Analgesics don’t work? (level I) TCAs, opioids & NSAIDs don’t work Pregabalin? Duloxetine? 2nd line, tramadol SR or tapentadol SR 3rd line, transdermal buprenorphine Oral steroids? Natural history; improvement in 3-6 months Pinto RZ et al. Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis. BMJ. 2012 Feb 13;344:e497. doi: 10.1136/bmj.e497.

Acute-on-chronic LBP flare-ups Rx as per acute LBP guidelines Comfort measures (heat) Continue baseline analgesia Celecoxib 100-200 mg bd for ≤ 4 days? Paracetamol w/ tramadol IR (or codeine?) prn Short-term IR opioid? (oxycodone) (≤ 4 days) Orphenadrine (?) or baclofen for muscle spasms (avoid diazepam) Four-hour rule for prn analgesia: ≤ 4/24 prn, ≤ 4 x daily, ≤ 4 days

Summary An inconvenient truth Pharmacotherapy: part of a multimodal pain Mx approach Not much works for CLBP or radicular leg pain Avoid opioids in CNSLBP (HARM > help) - consider in > 60s with spondylosis; or spondylitis - 3Ts: tramadol, tapentadol, transdermal buprenorphine - opioid ceiling dose = 90 mg oral morphine/eq per day - ‘opioid-non responsive pain’ (taper & cease, opioid rotation) Radicular pain: pregabalin, duloxetine, tramadol, tapentadol? Acute pain: celecoxib, paracetamol-combo prn Start low & go slow (↓ side effects)

Thank you

Pharmacotherapy for chronic NSLBP Learning objectives Pharmacotherapy must always be part of a multimodal pain Mx approach CLBP is often a ‘mixed’ pain (nociceptive & neuropathic pain elements) Analgesics are NOT that effective for CLBP Analgesics are NOT that effective for radicular leg pain Opioids are (essentially) contraindicated in CNSLBP (especially in < 60s) Exceptions: > 60s with ‘degenerative’ spinal pain (spondylosis), or patient w/ ‘inflammatory spinal pain’ (spondylitis) Preferred opioids, 3Ts: tramadol, tapentadol, transdermal buprenorphine Mx acute-on-chronic LBP flare-ups (multimodal, COX-2, paracetamol-analgesic combo) Avoid benzodiazepines Always titrate medications: ‘’start low and go slow’’

Visser MED 200 UNDA pain pharmacology 2015 Adverse effects of long-term opioids Classical side effects (respiratory, sedation, dizziness, nausea, constipation) Overuse (chemical-coping, addiction) (+ reward centre, dopamine) Opioid-induced hyperalgesia & tolerance (the pain gets worse) Endocrine changes (testosterone, osteoporosis) Immune modulation (activates glia via Toll-like receptors) Cortical changes on fMRI (cognitive, anxiety, mood, motivation) Increased all cause mortality Poor QoL, social & health outcomes >150mg oral morphine equivalents per day = really bad outcomes Visser MED 200 UNDA pain pharmacology 2015