79#7 neuro pharmacology and chronic pain

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Overview of the anatomical pathways of acute and chronic pain, detailed explaination of the synapse, and summary of various types of pharmacological agents for chronic pain

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79#7 neuro pharmacology and chronic pain

  1. 1. Neuro-Pharmacology of Chronic Pain Chapter 7 Nelson Hendler, MD, MS, Former Assistant Professor of Neurosurgery Johns Hopkins University School of Medicine Past president-American Academy of Pain Management www.DiagnoseMyPain.com Based on information from Hendler, N.: Pharmacotherapy of Chronic Pain Neurosurgical Management of Pain. Chap. 9: pp.117-129, ed. North, R., Levy, R., Springer-Verlag, New York, 1997 Hendler, N.: Pharmacological Management of Pain, Chapter 12 in Practical Management of Pain,pp. 145-155, Third edition, P. Prithvi Raj Editor, Mosby, St Louis, 2000.
  2. 2. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  3. 3. How A Nerve Works to Stop the Message of Pain • A message must be received by the brain to feel pain. • Nerves work by converting mechanical, chemical or electrical energy into an electrical nerve impulse. • This electrical nerve impulse travels until it reaches the end of the nerve at a synapse. • The synapse transfers information from electrical to chemical form to jump to the next nerve. The type of chemical lends specificity.
  4. 4. Neurochemical and Anatomical Pathway For Acute Pain (2 synapses) • Neo-Spino-Thalamic Tract (Acute Pain) BRAIN Spinal Cord sends message to the brain Peripheral Sensory Nerve (A beta, A delta, C fibers) carries the message to the spinal cord Mechano or pressure receptor (Meisner or Pachinian corpusule) or chemoreceptor (C fiber) in a finger Synapses (Chemically mediated) Thalamus Somato- Sensory Cortex (Pain) Chemical mediation lends specificity, and a site to manipulate
  5. 5. Neurochemical and Anatomical Pathway For Chronic Pain (Many areas of the brain are involved and multiple synapses- so this is slower transmission) • Palleo-Spino-Thalamic Tract (Chronic Pain) BRAIN Spinal Cord sends message to the brain Peripheral Sensory Nerve (A beta, A delta, C fibers) carries the message to the spinal cord Mechano or pressure receptor (Meisner or Pachinian corpusule) or chemoreceptor (C fiber) Synapses (Chemically mediated) Reticular Activating System Thalamus Hypothalamus Limbic System Somato- Sensory Cortex (Pain) Chemical transmission is slower than electrical transmission
  6. 6. Significance of Pathways of Pain • Pain patients have trouble sleeping due to pain, they get depressed, anxious, and they have pain. • Natural sleep (REM, stage 3 and stage 4) is caused by build-up of serotonin at the dorsal median raphe nucleus of the reticular activating system in the brain stem.
  7. 7. Other Neurosynaptic transmitters in the Brain • Biogenic Amines: dopa, dopamine, nor- epinephrine, epinephrine, serotonin. • 35% of neurosynaptic transmitters-GABA • 10% of neurosynaptic transmitters-Ach • 2%-5% of all neurosynaptic transmitters in the brain use biogenic amines • 95% of biogenic amines transmitters are in the hypothalamus and limbic system. • 90% of encephalins are in limbic system
  8. 8. Neurosynaptic Transmitters • Neurosynaptic transmitters can be inhibitory or excitatory, working by different mechanism of action • Neurosynaptic transmitters are made in the pre-synaptic area of the nerve • Various enzymes control the production or degradation of the neurosynaptic transmitters • MAO (monoamine oxidase) exists pre- synaptically, and makes transmitters • COMT (Catechol-0-methy-transferase)exists in the synapse and breaks down transmitters
  9. 9. Neurochemical and Anatomical Pathway For Chronic Pain • Palleo-Spino-Thalamic Tract (Chronic Pain) BRAIN Spinal Cord Peripheral Sensory Nerve (A beta, A delta, C fibers) Mechano or pressure receptor (Meisner or Pachinian corpusule) or chemoreceptor (C fiber) Sleep caused by serotonin Reticular Activating System Thalamus Hypothalamus Limbic System Somato- Sensory Cortex (Pain) Encephalin, 95% of biogenic amines
  10. 10. The Synapse and Neuro-Synaptic Transmitters (NST) • Pre-synaptic Synapse Post-synaptic • MAO makes NST COMT break down NST • 1)Transmitters are released from nerve A, 2) bind to the receptors, on nerve B, causing nerve B to fire, and 3) then reuptake occurs to stop the action of the NST. Post-Synaptic Receptor Sites Nerve transmission of information Nerve transmission of information Neuro-synaptic transmitter (NST) 1 2 3 1 COMT MAO BA
  11. 11. How medications works on the synapse • Pre-synaptic Synapse Post-synaptic • Increase activity by 1)Cause Release 2) Stop Reuptake 3)Mimic NST Post-Synaptic Receptor Sites Nerve transmission of information Nerve transmission of information Neuro-synaptic transmitter 2 3 1 I
  12. 12. How medications works on the synapse • Pre-synaptic Synapse Post-synaptic • Decrease activity by 1) Stop Release 2) Increase Breakdown 3)Block NST Post-Synaptic Receptor Sites Nerve transmission of information Nerve transmission of information Neuro-synaptic transmitter 3 1 COMT 2 2
  13. 13. The Axon and Cell Body • Transmission along a nerve, causing Na+ influx K+ Na+ Axoplasm Extracellular fluid Na+/K+ channelK+ comes out, Na+ goes in Pumps Na+ out, and K+ back in This entire process generates a current (90uV) across cell membrane
  14. 14. Mechanism of Action of Various Drugs • Medication can work at the synapse, which is very specific (there are 20 subtypes of serotonin receptors) • Medication can work on the nerve membrane (more non-specific). • Medication can inhibit natural transmitters by blocks release or receptor sites, • Medication can release transmitters, or block reuptake pre-synaptically.
  15. 15. Causes of Pain • Pain is produced when there is tissue damage • If there is sufficient heat, or pressure or cold, or stretching, or chemical damage to disrupt a cell, this causes the release of inflammatory chemical which irritate the pain fibers • Specific types of tissue have specific pains • Blood vessel compression causes a throbbing pounding pain, while muscle damage may cause spasm, or cramping pain, while nerve irritation may cause sharp, shooting pain
  16. 16. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  17. 17. Narcotics and How They Work • Mimic action of u1 and u2 morphine receptors to give pain relief. • Side effects: work on K1 and K2, S1 and S2 and enkephlin receptors in brain, gut, spinal cord, heart, etc., give respiratory depression, psychosis, low testosterone • Tachyphylaxis: excite their own break-down, so need more to keep working. • Receptor site upregulation so need more over time. • Used to control most acute pain –less useful in neuropathic (nerve) pain, and chronic pain
  18. 18. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  19. 19. Anti-Convulsants and How They Work • Cell membrane stabilization, Na+ channels. • Neurosynaptic transmitters- most GABA • Prevent cascade of protein synthesis to prevent “kindling.” (Uni. of Wisconsin). • Used to control nerve pain, neuropathic pain, peripheral neuropathy, trigeminal neuralgia, post-herpetic pain.
  20. 20. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  21. 21. Anti-Depressants and How They Work • Prevent reuptake of neurosynaptic transmitters. • This leaves more neurosynaptic transmitter at the post-synaptic receptor site. • Primarily block the reuptake of serotonin, and nor-epinephrine, and one works on dopamine (also stops smoking). • Used to helps sleep, depression, pain by working blocking encephalin hydrolyzing enzyme, leading to increased encephalins
  22. 22. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  23. 23. Muscle Relaxants and How They Work • Works centrally on glycine receptor, • Works peripherally on GABA receptor, at a spinal cord level. • Some like Zanaflex work by inhibiting the release of nor-epinephrine pre-synaptically • Used: to treat secondary muscle spasm, post-op spasm, acute injuries.
  24. 24. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  25. 25. Anti-Psychotics and How They Work • Post-Synaptic blockade of dopamine • Also inhibits the encephalin hydrolyzing agent, allowing accumulation of leucine and methionine encephalin, naturally occurring pentapeptide neurosynaptic transmitters with morphine like properties. • Used: for neuropathic pain, post-herpetic neuralgia, anti-anxiety
  26. 26. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  27. 27. Local Anesthetics and Neurotoxins and How They Work • Lidoderm Patch stabilized Na+ channels • Zostrix – may work on substance P. • Capsaisin – actually kills the small C fibers • Used: Local application for small C fiber mediated pain, which is most susceptible to local analgesic effect, mostly in the skin
  28. 28. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  29. 29. Anti-Anxiety Medications and How They Work • May work on GABA receptor in the brain, glycine receptor, and the benzodiazepine receptor. • Calms the patient • May cause intellectual impairment in 70% of patients (Hendler, Cimini, Ma, Long, Am. J. Psych, 1982). • Used: Pre-op relaxation, post-op relaxation.
  30. 30. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  31. 31. Vasco-Active Medications and How They Work • Inderal - beta blocking agent • Clonidine – partial alpha 2 agonist • Phenoxybenzamine –postsynaptic alpha 1 blocking agent • Phentolamine – post-synaptic alpha 1 blocking agent • Mexiletine – cell membrane inhibitor • Nifedipine – Calcium channel blocking agent • Used: headaches, CRPS II, Raynauds
  32. 32. Types of Medication Used for Pain • Narcotics • Anti-Convulsants • Anti-depressants • Muscle Relaxers • Anti-Psychotics • Local Anesthetics and Neurotoxins • Anti-Anxiety Medication • Vaso-Active Medication • Epidural Medication
  33. 33. Epidural Medication • Morphine –a u1 and u2 synaptic agent • Clonidine – a partial alpha 2 agonist • SNX-111 – a conotoxin - a calcium channel blocking agent that is orally degraded. From sea snail venom. • Dextromethorphan- work on NMDA receptors • Kappa 2 agonist – for neuropathic pain • Used: in an implantable pump, for spinally mediated pain
  34. 34. Issues With Chronic Narcotics • Psychological Addiction • Physiological Habituation • Intellectual Impairment (Hendler, Am J. Psych) • Diversion (Rudy Giulliani- Rx Action Alliance) • Loss of Sexual Activity (Hendler testosterone studies) • Physician Concerns (DEA directives)
  35. 35. Narcotics Problems • Constipation • Not particularly effective in neuropathic pain, i.e. nerve entrapments, CRPS I, radiculopathies, trigeminal neuralgia, peripheral neuropathies. • Dosage escalation. • Patient compliance. • Need for a contract.
  36. 36. Narcotics Problems Routes of administration-oral, nasal,rectal, IM,TC. Transcutaneous- skin thickness, hair, temperature, adhesives, variable absorbsion rates, sweating, compliance, (One colleague told me he told a patient to apply a patch q 2 days, and gave him a 90 day supply. The patient returned complaining he is running out of room to put patches. Yes- indeed- he had 45 patches on his body. Now instructions include remove the old patch before applying the new one).

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