Clinical Pharmacology of Pain Eija Kalso, MD, DMedSci

Transcription

1 Professor of Pain Medicine University of Helsinki 1 Drugs used in pain management Paracetamol (acetaminophen) NSAIDs Non-selective (inhibit both COX-1 and COX-2) Those that inhibit COX-2 only ( coxibs ) Opioids weak opioids codeine tramadol strong opioids morphine oxycodone fentanyl methadone 2 Drugs used in pain management (2) Drugs that enhance endogenous pain control 5-HT NA (NE) Antidepressants and anxiolytic effects Drugs that block Na + -channels Local anaesthetic agents (lidocaine) Many antiepileptics (carbamazepine) TCAs (amitriptyline, nortriptyline) Ca ++ -channel modifiers Gabapentinoids Most drugs have several mechanisms of action 3 1

2 Orally, if possible S.C. or T.D. Route of drug administration If oral administration is not possible To reduce adverse effects I.T. To the CSF Opioids (and some other drugs) Mainly in cancer pain Topically NSAIDs (strains and sprains, osteoarthritis) Lidocaine (neuropathic pain) Capsaicin (neuropathic pain, OA) Opioids 4 Pharmacological management of pain: How to choose the right analgesic? Acute pain or chronic pain Mechanism based Cancer pain or non-cancer pain Evidence-based Tailored for the individual patient 5 Pharmacological management of pain: How to choose the right analgesic? (2) Acute pain Acute pain can be severe but it usually lasts for a few days only Fast recovery of function with good pain relief without adverse effects is the main goal Paracetamol (acetaminophen) and/or NSAIDs form the basis for acute pain management Opioids are used when needed Oral administration is preferred 6 2

3 Pharmacological management of pain: How to choose the right analgesic? (3) Mechanism based 7 Nociceptive Pathological Normal Inflammation Neuropathy Paracetamol/acetaminophen NSAIDs Opioids Pain Antidepressant Anticonvulsants Opioids 8 Cancer pain consists of nociceptive pain + inflammatory pain + neuropathic pain + visceral pain + bone pain + psychosocial factors = cancer pain 9 3

4 Pharmacological management of pain: How to choose the right analgesic? (4) Cancer pain Fig. 1. The three-step analgesic ladder 10 Modified WHO ladder special techniques: ketamine, SC infusion/pca spinal analgesia: morphine, bupivacaine, clonidine baseline: CR oxycodone/morphine TD fentanyl/methadone breakthrough: IR oxycodone/morphine TM fentanyl buprenorphine (SL, TD) tramadol, codeine NSAID/paracetamol (acetaminophen) neuropathic pain: amitriptyline, gabapentin/pregabalin, others; treatment of nausea and constipation 11 Absorption of fentanyl through the skin Figure 1. Dose-adjusted plasma fentanyl concentrations (mean ± SEM) epidermis dermis 0.30 * capillary * * e)x10 4 Concentration(mg/L/dos Time (h) Normal weight Cachectic *P <0.05 Heiskanen T. et al., Pain

5 Pharmacological management of pain: How to choose the right analgesic? (5) Evidence-based 13 At least 50% pain relief over 4-6 hours Pain relief was measured on a scale of 0-10 for 6 hours P Cod 60 Ibuprofen 400 Ibuprofen 200 Morphine 10 (IM) Aspirin 1000 Paracetamol 1000 Aspirin 600/650 Tramadol 100 Paracetamol 600/ NNT (95%CI) McQuay HJ & Moore RA 14 1 Diclofenac Ibuprofen Paracetamol NNT ,000 10,000 oral dose (mg) McQuay H and Moore RA,

6 Interindividual variation of PTGS1 and PTGS2 expression at 2 to 4 h after surgery level (log 2 ) Expression l PTGS1 PTGS2 Fold change Increase Decrease Lee YS et al., Analgesic response at 48h after surgery according to polymorphisms in the PTGS2 after administration of ibuprofen or rofecoxib VAS) Ibuprofen Rofecoxib Pain (100 mm CC+CG GG PTGS2SNP2 Lee Y-S et al., NNT for one patient with pain of moderate or severe intensity to achieve at least 50% pain relief compared with placebo Diclofenac 50 Naproxen 440 Ibuprofen 400 Morphine 10 IM Paracetamol codeine 60 Paracetamol dextropropoxyphene 65 Aspirin 650 Paracetamol 1000 Tramadol 100 Paracetamol 650 Dextropropoxyphene 65 Codeine 60 Total in comparison Number needed to treat 18 6

7 Pharmacokinetics of codeine and its metabolite morphine Kirchheiner J et al., Pharmacogen 2007; 7: Population UM fr (%) AUC (morphine)/a AUC (codeine) Scandinavia 1-2 Middle-Europe 4-5 North-America 4-5 Mediterranean 7-12 Asia Saudi-Arabia 21 Ethiopia 29 Breastfeeding and codeine - CYP2D6 UM - UGT2B7*2/*2 (M6G:M) CYP2D6 fine activity 19 Tramadol O-demethylation to M1-metabolite (opioid) via CYP2D6 PM: more serotonin effect? PM: less effect in experimental (Poulsen et al., 1996) and clinical pain relief (Stamer et al., 2003) UM: ventilatory depression (tramadol 500 mg IV in 5 hours, creatinine 200 μmol/l) (Stamer et al., 2008) 20 Pharmacogenetics of analgesics Non-steroidal anti-inflammatory drug analgesia Opioid analgesia Glycoprotein P: transport through membranes COMT: modulation of the opioid system? CYP 450 isoenzymes: metabolism MC1R OPRM1: target receptor function 21 7

8 Human mu opioid receptor gene SNPs 118A>G 118A>G N40D 22 COXIBs Vane & Botting Adverse effects of NSAIDs Allergic reactions Gastric irritation, mucosal damage, G-I bleeding Reduced kidney function Cardiac failure Reduced platelet function Thromboembolic complications 24 8

9 Endogenous opiates and behavior Pain and analgesia Stress and social status Learning and memory Eating and drinking Alcohol and drugs of abuse Sexual activity and hormones Pregnancy Development and endocrinology Mental illness and mood Seizures and neurological disorders Gastrointestinal function Renal function Hepatic function Cardiovascular responses Respiration Thermoregulation Immunological responses 25 Nomenclature of opioid receptors ORL 1 OP 4 NOR NOP receptor μ-opioid receptor OP 3 MOR MOP receptor δ-opioid receptor OP 1 DOR DOP receptor κ-opioid receptor OP 2 KOR KOP receptor 26 Opioid receptor binding and activation [ 3 H]-Diprenorphine displacement (nmol/l) [ 35 S]GTPγS binding to hmor1 Ligand hmor1 mdor1 hkor1 EC 50 (nmol/l) E max (%) Oxycodone 16 >1000 > Oxymorphone Morphine Fentanyl Methadone DAMGO DPDPE 2.0 U

10 P-glycoprotein A B Cerebrospinal fluid Choroid plexus 28 Log octanol/water partition coefficients of opioids at 25 C ph 7.0 ph 7.4 ph 8.0 Morphine Oxymorphone Oxycodone Fentanyl Sufentanil Pharmacokinetic aspects of opioids Opioid Terminal half-life (h) Clearance (L/min) Oral bioavailability (%) Morphine Methadone Fentanyl <2/90 (TD) Oxycodone 3.5 ± Hydromorphone Codeine Tramadol Buprenorphine 70 (SL) 30 10

11 Transfer half-lives of opioids between plasma and brain in humans Lötsch J et al., Clin Pharmacokinet 2006; 45: Opioid Morphine M-6-G Hydromorphone Oxycodone (L)-methadone Fentanyl Alfentanil Remifentanil Transfer half-life h h min 11 min 7.7 min min min min 31 Important half-lives of opioids Absorption site: IV/PO/TD Plasma Brain Opioid Transfer half-life (P B) t 1/2, ke0 Elimination half-life (t 1/2, z) Morphine h 2-4 h Oxycodone 11 min 4-8 h (L)-methadone 7.7 min h Fentanyl min 3.5 ± 0.8 h 32 Pharmacokinetics of opioids Opioid Metabolic route Active metabolies Morphine UGT 1A1/2B7 M6G Methadone CYP 1A2/2B6/2C19/2D6/3A4/5 No Fentanyl CYP 3A4 No Oxycodone CYP 2D6 /3A4/5 Oxymorphine Hydromorphone UGT 1A1/2B7 No Codeine CYP 2D6/3A4 Morphine Tramadol CYP 2B6/2D6/3A4 M1 Buprenorphine CYP 3A4 & UGT 1A1/2B

12 Metabolism of oxycodone α-oxycodol β-oxycodol 9,2% 6,8% α-noroxycodol Oxycodone CYP 2D6 α-oxymorphol CYP 3A4 20% 100% 0,8% Noroxycodone Oxymorphone 74% 2,9% CYP 3A4 β-noroxycodol CYP 2D6 β-oxymorphol 5% Noroxymorphone 1,1% 21% Lalovic B et al., Clin Pharmacol Ther Oxycodone: CYP 3A4 Hagelberg et al., Mean SEM plasma concentrations after 10mg of oral oxycodone Liukas et al., CPT 2008 Age CL/F tmax Cmax t1/ o yrs yrs yrs yrs UM oem PM Time (h) Time (h) 36 12

13 Equianalgesic doses Single doses 1:1 Long-term administration 6-14:1 Methadone can be an effective analgesic when other opioids have failed due to tolerance Morphine Methadone Ratio 37 Pharmacokinetics of methadone Lipophilic Protein binding 85% Oral bioavailability 80% (41-99%) Fast distribution in 2-3 hours Duration of effect 4-8 hours Long elimination half life hours 38 Elimination of methadone Metabolism through CYPs 1A2, 3A4, 2D6 CYP 3A4 is inducible CYP 2D6 is polymorphic Metabolites are inactive No accumulation in renal insufficiency Clearance is increased in low ph of urine 39 13

14 Drug interactions Methadone increases the concentrations of: Desipramine & zidovudine The clearance of methadone is inhibited by: Fluconazole, ketoconazole Fluoxetine, fluvoxamine Ciprofloxacin The clearance of methadone is induced by: Carbamazepine, phenobarbital, phenytoin Fusidic acid, rifampicin Ritnavir, nevirapine 40 Adverse effects of opioids How to treat? Respiratory depression Sedation Nausea and vomiting: haloperidol Constipation: laxatives, naloxone, methylnaltrexone Urinary retention Miosis Sweating Pruritus 41 Prevalence 1-2 (8)% Peripheral and central Causes: Trauma Surgery Ischaemia Stroke Infections Herpes zoster/simplex, HIV Metabolic diseases Diabetes Toxic substances Chemotherapy Paraneoplastic symptoms Neuropathic pain 42 14

15 TCA Amine pump NA receptor NA (NE) 5-HT receptor 5-HT NMDA receptor Glutamate Na + -channel Na + Brain Brainstem Spinal cord DOPA NA (NE) 5-HT DRG Sindrup et al., Treatment of peripheral neuropathic pain: Evidence of efficacy Finnerup, Antidepressants Tricyclic antidepressants NNH = 15 Amitriptyline, nortriptyline, imipramine, clomipramine, doxepin SNRI Venlafaxine, duloxetine, milnacipran NaSSA Mirtazapine SNaRI Reboxetine SSRI Citalopram, fluoxetine, paroxetine 45 15

16 Neuropathic pain conditions: antidepressants Condition Studies with positive or negative outcome Diabetic neuropathy F PHN HIV Chemotherapy Traumatic Phantom limb pain Trigeminal neuralgia A A A A A A V Spinal cord injury Central post stroke pain A A 46 Mechanisms of action of antidepressants used in neuropathic pain 47 Drug Tricyclics Venlafaxine Duloxetine Mirtazapine Drug interactions Pharmacokinetic aspects CYP 1A2, 2D6, 3A3/4, active metabolites Metabolized by CYP 2D6 to 0-desmethylvenlafaxine (active), venlafaxine is a weak inhibitor of CYP 2D6 and 3A4 Metabolised by CYP 1A2 and CYP 2D6 Metabolised by CYP 2D6 and 1A2 (3A4, carbamazepine ind.), it does not inhibit CYP 2D6,1A2, or 3A4 Milnacipran Conjugated to glucuronides, low protein binding Reboxetine Extensively bound to plasma proteins, no effects on CYP 2D6, metabolised by 3A4 Citalopram Weak inhibitor of CYP 2D6, metabolised by CYP 3A4 Paroxetine Very strong inhibitor of CYP 2D6 Fluoxetine Strong inhibitor of CYP 2D6, 2C9/10, inhibits CYP 3A3/

17 Ca ++ -channel modifiers as analgesics: Gabapentin & pregabalin 49 Mechanism of action Gabapentinoids bind to the α 2 δ-subunit of voltage-gated Ca ++ -channels Dorsal horn of the spinal cord Frontal cortex Ca ++ -influx in hyper-excited neurons Pre-synaptic inhibition of the release of neurotransmitters NA (NE) Glutamate sp 50 Gabapentinoids Gabapentin and pregabalin Relieve pain and anxiety, improve sleep Anticonvulsant action Less effective than some antidepressants in neuropathic pain No liver metabolism No pharmacokinetic interactions Safe in drug combinations, OBS: kidney function! Different adverse effect profile compared with antidepressants Pregabalin: Non-saturable absorption Linear pharmacokinetics Less variation in absorption Twice daily administration Fast onset of action 51 17

18 Neuropathic pain conditions: Gabapentin/pregabalin Condition Studies with positive or negative outcome Diabetic neuropathy PHN HIV Chemotherapy Traumatic Phantom limb pain Trigeminal neuralgia Spinal cord injury Central post stroke pain 52 Na + -channel blockers as analgesics: Lidocaine, (mexiletine) and anticonvulsants 53 Mechanisms of action of anticonvulsants used in neuropathic pain 54 18

19 Topical analgesics: Lidocaine and capsaicin 55 Cold, warm and hot sensations are mediated through different channels; each channel has an individual threshold temperature; several substances can activate them Isothiocyanates Capsaicin in hot chili peppers in horseradish Camphor in the laurel tree Camphor in the laurel tree Bisandrographolide in a Chinese herb Menthol in green mint Cinnamaldehyde in cinnamon Allicin in garlic >53 C >43 C >33 C >25 C <23 C <17 C Szallasi et al., New indications for adjuvant drugs Perioperative use Gabapentin/pregabalin Dierking et al., 2004; Pandey et al., 2004; Rorarius et al., 2004; Turan et al., 2004; Gilron et al Ketamine McCartney et al., 2004; Elia et al., 2005; Bell et al., 2005 Dextromethorphan McCartney et al., 2004 Prevention of chronic pain Amitriptyline for PHN: 25mg for 3 months Bowsher D,

20 Use of opioids in chronic non-cancer related pain: Symptom control is not the only goal the patient s functional status should also improve Oxycodone: ~ 40mg/day Morphine: ~ mg/day Kalso E et al., Pain Opioids in chronic non-cancer pain: Systematic review on efficacy and safety Kalso et al., Pain 2004 At least one adverse effect was reported by 81% with opioids (52% with placebo) with an NNH of 3.4 ( ) Most commonly reported adverse effects were: Constipation (42%) Nausea (32%) Somnolence (29%) Dizziness (20%) Vomiting (16%) Itching (15%) Dry mouth (14%) 59 Treatment duration in responders and non-responders All subjects Non-responders (30%) Responders (30%) % of pat tients Kalso E. et al., BMC Medicine, 2007 Treatment duration (days) 60 20

21 Constipation Somnolence Sweating Pruritus Nausea rticipants % Par Time (days) FEN SRM FEN SRM 1 FEN SRM FEN SRM FEN SRM FEN SRM FEN SRM FEN SRM Severe Moderate Mild Kalso E. et al., BMC Medicine, Other concerns Tolerance Abuse Hyperalgesia Endocrinological effects Hypogonadism Guidelines Careful patient selection and follow-up Short duration only 62 Combinations Paracetamol/acetaminophen + COX-2- inhibition + Opioids Na + -channel block + Cathecolamines (NE) + Serotonin + NMDA-antagonists (glutamate) + Gabapentinoids 63 21

22 Pharmacological management of pain: How to choose the right analgesic? (6) Tailored for the individual patient: Type of pain Duration of pain Pharmacogenetics Other drugs and treatment Adverse effects Cost 64 New targets N-type Ca ++ -channel blockers: ziconotide (i.t.): for severe treatment resistent chronic pain Cannabinoids: MS? NGF-antagonists: OA, cancer pain neuropathic pain? Microglia: neuropathic pain, opioid hyperalgesia? Minocyclin, amitriptyline PDEI TLR4 antagonists 65 Guidelines Acute pain management (several) Opioids in cancer pain Opioids in non-cancer pain Neuropathic pain 66 22

23 References Acute pain: Acute Pain Management: Scientific evidence, 2nd edition; Opioid and cancer pain: Morphine and alternative opioids in cancer pain: The EAPC recommendation; Br J Cancer (2001); (These guidelines will be updated in 2010) Opioids and chronic non-cancer pain: (UK) Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain; J Pain (2009) (USA) Neuropathic pain: Pharmacological management of neuropathic pain: Evidence-based recommendation; Pain (2007) EFNS guidelines on pharmacological treatment of neuropathic pain; Eur J Neurol (2006); (These guidelines have been updated and will be published in 2010)