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Home , Allodynia, Hypoalgesia, Norpethidine, Sodium channel blocker

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 Neurochemistry of and Adjuvants for Pain Therapy  Early pain treatment can reduce  May help avoid acute pain progressing to Chuthamanee C. Suthisisang BPharm, PhD  Clinical pharmacology of Department of Pharmacology analgesics and adjuvants Faculty of Pharmacy Mahidol University

Cortical areas that received SENSATIONS information from

location, affective duration component and intensity

INPUTS

REFLEXES

Multiple mediators at the site of injury C-fiber

  2 5-HT3  5-HT2 Glu GABAB SP SP Glu

Ca++ Na+

NMDA AMPA GABA GABA   2 B A 5-HT3 5-HT2

Increase + Dorsal horn Increase Na influx Ca++ influx Intracellular events leading to Spontaneous central sensitization Tissue damage pain

Glutamate

PERIPHERAL CENTRAL FMS ACTIVITY SENSITIZATION

Decreased Increased Nerve damage threshold to Expansion of spontaneous peripheral receptive activity stimuli field Secondary hyperalgesia

Analgesic classification C-fiber 1.  no ceiling effect except partial and mixed -antagonist   2 5-HT3  5-HT2 2. Non-opioids GABA B  NSAIDs/Coxibs ceiling effect 3. Adjuvant or coanalgesics (diverse

Tizanidine group of medications that enhance the effects of typical analgesic medications or provide analgesia for certain types of pain)  NMDA AMPA GABA GABA tricyclic   2 A B 5-HT3 5-HT2  antiepileptics Dorsal horn  steroids  bisphosphonates, calcitonin

WHO Analgesic ladders Analgesic selection

 severe, acute pain ---> strong opioids + coxibs Strong -  moderate, acute pain ---> weak opioids + Non - opioid Pain persisting or  mild, acute pain ---> non-opioids increasing + Adjuvant  mild chronic noncancer pain e.g. Weak - opioid ---> NSAIDs + Non - opioid Pain persisting or  severe chronic noncancer pain e.g. back pain increasing + Adjuvant ---> strong opioids + NSAIDs/ coxibs

---> , Non - opioid Acute pain ---> , + Adjuvant Multimodal Analgesia COX-2 and peripheral sensitization

A N E X A M P L E Tissue Injury Opioid Firing Threshold Decreases   doses of each analgesic COX-2 Expressed  Improved anti- EP Potentiation due to synergistic/ PKA additive effects PGE 2 PKC  May  severity of side  effects of each NSAIDs, Increased COX‐2 inhibitors, P regional blocks, neuronal membrane SNS/PN3 α2‐agonist, excitability TTx resistant channel

Adapted from Kehlet H, Dahl JB. Anesth Analg., 1993;77:1048–1056.

Role of in Pain COX-2 Inhibition and A Working Hypothesis sensitization

Peripheral Central  Signal for COX-2 induction likely to persist with Trauma / Pathophysiologic conditions peripheral inflammation (eg hypoxia, ischemia) or PLA2 IL-1 IL-6? inflammatory stimuli  To minimize sensitization, COX-2 should be Release of PGES? inhibited centrally and in the periphery induction of COX-2 Induction of COX-2  IL-1 as early as possible Prostaglandins  continued until peripheral inflammation resolved Prostaglandins Central sensitization  Ideal COX-2 inhibitor should be able to act in periphery as well as centrally Sensitivity of peripheral Abnormal pain sensitivity  should readily cross the blood-brain barrier

PAIN

Chemical classes of NSAIDs NSAIDs half-life and their and COXIBs maximum dose

Nature Reviews Drug Discovery 2007;5:75-85 Chemical structures of COX-2 inhibitors an injectable prodrug of

Parecoxib (Prodrug) Valdecoxib (Active) (Celebrex) (Vioxx) Hydrolysis

Sulfones Sulfonamides (-) Na+ (Arcoxia) Glucuronidation Hydroxylation Valdecoxib (3A4, 2C9) (Bextra) Glucuronide Glucuronide Active Hydroxylated (Sulphonamide) () Metabolite

Walter MF, Mason RP. Atherosclerosis 2004;177:235-243

Major NSAIDs adverse effects Preferential COX-2 inhibitors

 GI bleeding  Renal (pre-existing or kidney disease, use of  loop diuretics, or loss of more than 10% of blood  volume)  Congestive heart failure (prior history of heart  disease, renal failure, DM or )   Dermatologic (Urticaria, , Stevens- Johnson syndrome, exfoliative dermatitis)  Acetaminophen (FASEB J 2008; 22 :383-90 ) switch to other chemical classes  Respiratory (Bronchospasm, status asthmaticus) Stop NSAIDs (do not switch to other chemical classes, switch to meloxicam, nimusulide, COXIBs)

COXIBs adverse effects Strategic for use of NSAIDs/COXIBs  from plasma volume expansion (esp high dose)  Prescribe NSAIDs/COXIBs to patients at low risk of thromboembolic events  Acute kidney injury (Caution should be used when initiating treatment with parecoxib in patients with dehydration. In this case, it is  Minimize duration of treatment with advisable to rehydrate patients first and then NSAIDs/COXIBs to decrease of risk start therapy with parecoxib; keep adequate hydration)  Prescribe the lowest effective dose

 CVS  Monitor BP, edema, renal function, GI bleeding

 GI: delay ulcer healing Circulation 2005;112:759-70 Drug-drug Interaction of NSAIDs/COXIBs Weak Opioids  Pharmacodynamics drug interactions

 Antagonism

and attenuates antiplatelet activity of low dose

 Increasing ADRs  (max dose 240-360 mg/d)  Plasma volume expansion: antidiabetics (pioglitazone, high dose  sulfonylureas)

 Increasing bleeding risk: corticosteroids/antiplatelets/anticoagulants  (max dose 400 mg/d)

 Pharmacokinetics drug interactions

 CYP2C9 inhibitors, such as ,fluconazole, isoniazid, sulfamethoxazole and may increase plasma level of some NSAIDs/COXIBs (ibuprofen, indomethacin, , celecoxib, valdecoxib, , , meloxicam and )

Tramadol Characteristics Tramadol maximum dose per day

• Weak mu and kappa receptor agonist (Approximate 1/10 as potent as morphine)  Adult dose : 400 mg/day  O-desmethyl metabolite (M1 metabolite) 6 times more potent than tramadol, half life 7.4 h  Over age 75 years : 200-300 mg/day  Renal Insufficiency (CrCl <30 ml/min)  Inhibit 5-HT and NE reuptake (induce nausea, dizziness and ) - Reduce dosing frequency to every 12 hours - Do not exceed 200 mg per day  M1 excreted via kidney unchanged and may increase respiratory depression in renal failure

 Reduce seizure threshold, increase seizure risk with SSRI, TCAs

Metabolism of codeine Opioid Clearance is Reduced in Renal Diseases

codeine CYP2D6 morphine  Morphine : accumulation of M6G CYP2D6 CYP2D6  : accumulation of norpethidine (active metabolite, half life 30 h) CYP2D6

 Tramadol : accumulation of M1 CYP3A4

conjugation  : accumulation of noroxycodone norcodeine and/or and elimination used in neuropathic pain Symptoms of neuropathic pain

blockers  antiepileptics ( , carbamazepine, )  local anaesthetics ( ) 1. Negative symptoms  (diminished sensitivity to pain or  Antidepressants (enhance descending inhibitory pathway) stimulation)  Drugs that enhance GABA function   gabapentin, ,  Drugs that block specific N-type Ca Channel  gabapentin, , pregabalin  NMDA antagonists  Opioids

Symptoms of neuropathic pain Peripheral mechanisms of (cont.) neuropathic pain

2 . Positive symptoms  Up-regulation of Na+ channel and 2.1 Spontaneous sensations channel (stimulus-independent pain)  Ectopic discharge  continuous (burning, stabbing)  Ephaptic cross talk (transfer of nerve impulse  paroxysmal (shooting, lancinating) from one to anothers)  spontaneous abnormal sensation ( and ) Ephases = abnormal electrical connections occurred 2.2 Evoked sensations (stimulus-evoked pain) between adjacent demyelinated  hyperalgesia  Sympathetically maintained pain (ephapses  allodynia between sensory and sympathetic fibers)  Neurogenic inflammation following neural injury

Calcium channels plasticity N-type calcium channels and pain

 Found almost exclusively on especially at high levels in the presynaptic terminals  Neuropathy induces plasticity - N-type enhanced  Complexed with proteins that are involved in secretion, including syntaxin, - No changes in P- and T-type synaptotagmin and SNAP-25 - No role of L-type

 α1B and α2δ1 subunits are upregulated in DRG neurons following or tissue inflammation  Inflammation induces plasticity - N-type and P-type enhanced Pregabalin binds to the 2- subunit Structures of gabapentinoids of voltage-gated calcium channels

Pregabalin binds here 2

1 extracellular   II I III IV Lipid bilayer

cytoplasmic Pregabalin is a lipophilic analogue of GABA substituted at the 3-position to facilitate diffusion across the blood–brain barrier. II- Binds to neurons at the 2- subunit of voltage-gated III  calcium channels (brain and spinal cord) Nature Rev Drug Disc 2005;4:455 Arikkath J, Campbell KP. Curr Opin Neurobiol 2003; 13: 298-307

C-fiber C-fiber

N-type N-type Ca++ channel Ca++ channel Glu SP Glu SP SP Glu SP Glu

Ca++ Ca++ Na+ Gabapentinoids X X

NMDA AMPA NK1 NMDA AMPA NK1

Increase Decrease + Na influx Dorsal horn Ca++ influx Dorsal horn Increase Ca++ influx

 - modulators: differences 2 Central mechanisms of between pregabalin and gabapentin neuropathic pain

Pregabalin Gabapentin  Central reorganization of Ab fibers activity (rat 1.3 mg/kg (ED50) 9.1 mg/kg (ED50) (sprouting of Ab from lamina III to electroshock) lamina I,II) Neuropathic pain 3 mg/kg (MED) 10 mg/kg (MED) activity (rat )  mRNA for SP and NK1 receptors Non-saturable across Absorption Saturable  dose range opioid binding sites  Oral bioavailability ≥90% ≤50% Central sensitization  Loss of inhibitory Excretion renal renal Tricyclic antidepressants The descending inhibitory pain pathway

 Inhibit 5-HT and NE reuptake  Cortex 1 antagonist Opioids  +/- + + PAG +/- Hypothalamus  histamine antagonist Opioids + + + NRPG + NRM LC DLF Noradrenaline Amitriptyline – – – 5-HT Dorsal horn is also potent 5-HT antagonist, Nociceptive 2A afferent fibres – NMDA and Opioids sodium

Locus coeruleus Raphe nuclei Locus coeruleus Raphe nuclei

Amitriptyline

Amitriptyline Venlafaxine Duloxetine Duloxetine Tramadol

NE 5-HT Tramadol NE 5-HT

5-HT at synapse NE at synapse

5-HT1A 5-HT1A 2 2 Dorsal horn Dorsal horn Nociceptive Nociceptive afferent fiber afferent fiber

Inhibit DH activation Inhibit DH activation

Drug Dosage Undertreated Pain

 Amitriptyline: start with 10-25 mg hs and titrate q 3 d up to 75-150 mg/d; evaluate at 1-2 weeks for therapeutic and side effects

 Gabapentin: start with 100 or 300 mg hs and titrate by 300 mg q 3 or 7  Negative emotions – anxiety,depression d up to 1800-3600 mg in 3 divided doses; first follow up in 2 weeks  Sleep deprivation  Pregabalin: start with 50 mg hs and titrate up to 300 mg/d within 1 week based on efficacy and tolerability  Existential  Adverse immunological sequale  Tramadol: start with 37.5 or 50 mg hs and titrate up to 200-400 mg/d in 3 divided doses Impaired immune response   Duloxetine: start with 30 mg OD and titrate up to 60-90 mg Decreased natural killer cells