PHARMACOLOGICAL MANAGEMENT OF PAIN update - Copy

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DR.S.SREENIVASARAO MD,C.C.P.P.M, ASSIST PROFESSOR, DEPT.OF ANAESTHESIA, S.V.R.R.G.G.H.&S.V.M.C, TIRUPATI PHARMACOLOGICAL MANAGEMENT OF PAIN

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Mera jeevan kora kaagaz kora hi reh gaya -2 Jo likha tha ………………………………………… ….. Dard sah ke janm leta Har koi insan -2 Vo sukhi hai -2 Jo khushi se dard sah gaya Mera jeevan kora kaagaz kora hi reh gaya movie- kora kaagaz (1974) singer- kishorekumar music- kalyanji Anandji Lyricist - M. G. Hashmat ; SVRRGGH&SVMC

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NEED OF PAIN MANAGEMENT ? WHAT IS PAIN & TYPES ? MANAGEMENT OF NOCICEPTIVE PAIN MANAGEMENT OF NEUROPATHIC PAIN NONPHARMACOLOGICAL MANAGEMENT OF PAIN SVRRGGH&SVMC

NEED OF PAIN MANAGEMENT ???:

NEED OF PAIN MANAGEMENT ??? SVRRGGH&SVMC

Consequences of Unrelieved Pain:

Consequences of Unrelieved Pain Myocardial ischemia Increased sympathetic activity Myocardial O 2 consumption  GI effects Splinting, shallow breathing In creased catabolic demands Anxiety and fear Peripheral/ central sensitization GI motility  Atelectasis, hypoxemia, hypercarbia Poor wound healing/muscle breakdown Sleeplessness, helplessness Available drugs Delayed recovery Pneumonia Weakness and impaired rehabilitation Psycho- logical Chronic pain Acute Pain Courtesy of Sunil J Panchal , MD SVRRGGH&SVMC

Intensity of Pain After Discharge: 81% Report Moderate to Extreme Pain :

21% 8% 19% 52% Intensity of Pain After Discharge: 81% Report Moderate to Extreme Pain Slight Moderate Severe Extreme Pain Intensity Apfelbaum et al. Anesth Analg. 2003;97:534-540. SVRRGGH&SVMC

WHAT IS PAIN………?:

WHAT IS PAIN………? DEFINITION : “ An unpleasant sensory and emotional experience associated with actual or potential damage or described in terms of such damage” - International Association for the Study of Pain, 1979 PAIN IS SUBJECTIVE REACTION TO AN OBJECTIVE STIMULUS ( Merskey , Bogduk 1986). WHAT THE PATIENT SAYS – “HURTS” SVRRGGH&SVMC

PAIN -TYPES:

PAIN -TYPES NEUROPATHIC COMPONENT N C O O C M I P C O E N P E T N I T V E YES NO YES MIXED NOCICEPTIVE NO NEUROPATHIC DYSFUNCTIONAL SVRRGGH&SVMC

Total care:

Total care emotional spiritual physical social ‘‘ Pain management continues to be the most difficult problem facing medicine today.’’ Jason R. Bauer and Charles E. Ray, Jr. WHY ………….? SVRRGGH&SVMC

WHAT HAPPENS WHEN TISSUE INJURY OCCURS ??? :

WHAT HAPPENS WHEN TISSUE INJURY OCCURS ??? PRIMARY HYPERALGESIA SECONDARY HYPERALGESIA Central sensitization Peripheral sensitization SVRRGGH&SVMC

Modified WHO Analgesic Ladder:

Pain Step 1 ± Nonopioid ± Adjuvant Pain persisting or increasing Step 2 Opioid for mild to moderate pain ± Nonopioid ± Adjuvant Pain persisting or increasing Pain persisting or increasing Step 3 Opioid for moderate to severe pain ± Nonopioid ± Adjuvant Invasive treatments Opioid Delivery Quality of Life Modified WHO Analgesic Ladder Proposed 4 th Step The WHO Ladder Deer, et al., 1999 SVRRGGH&SVMC

NOCICEPTIVE PAIN/ACUTE PAIN:

NOCICEPTIVE PAIN/ACUTE PAIN AIM TO DECREASE THE INFLAMMATORY MEDIATORS AND THEIR EFFECTS TO STOP THE IMPULSE TRANSMISSION TO DECREASE THE INFLAMMATORY SIGNS LIKE OEDEMA SVRRGGH&SVMC

DRUGS USED FOR ACUTE PAIN:

DRUGS USED FOR ACUTE PAIN NSAIDS COX-2 INHIBITORS ACETAMINOPHEN OPIOIDS & OTHERS SVRRGGH&SVMC

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Modes of action of analgesics 1,2,3,4 1 . D’Amours RH et al. JOSPT 1996;24(4):227-36. 2. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4. 3. Pini LA et al. JPET 1997;280(2):934-40. 4. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31. Opioids  Activation of opioid receptors Paracetamol  Inhibition of central Cox-3 (?) (Inhibition of PG synthesis ) Paracetamol  Interaction with serotoninergic descending inhibitory pathway NSAIDs / Coxibs  Inhibition of peripheral and central Cox-1 / Cox-2 (Inhibition of PG synthesis ) SVRRGGH&SVMC

NSAIDS:

NSAIDS Salicylates -Aspirin p-amino phenol derivatives - Paracetamol Propionic acid derivatives- Ibuprofen Acetic acid derivatives- Indomethacin, Diclofenac,Ketorolac Oxicam derivatives- Piroxicam ,Meloxicom Fenamic acid derivatives- Mefeamic acid Cox-2 inhibitors- Celecoxib ,Valdecoxib Sulphonanilides- Nimmesulide Others- Licofelone SVRRGGH&SVMC

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Antiinflammatory Antipyresis Analgesia Prototype Chemical Class +++ +++ +++ Aspirin Salicylates Marginal +++ +++ Acetaminophen Para - aminophenols ++++ ++++ +++ Indomethacin Indoles +++ +++ +++ Tolmentin, mefenamic acid Pyrrol acetic acids ++++ +++ ++++ Ibuprofen, naproxen Propionic acids ++++ +++ +++ Phenylbutazone, piroxicam Enolic acids +++ ++ ++ Nabumetone Alkanones ++++ +++ ++++ Celecoxib Sulfonamide SVRRGGH&SVMC

ALL ARE SAFE TO USE ????????????????? :

ALL ARE SAFE TO USE ????????????????? SVRRGGH&SVMC

MECHANISM OF ACTION:

MECHANISM OF ACTION SVRRGGH&SVMC

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SVRRGGH&SVMC

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SVRRGGH&SVMC

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SVRRGGH&SVMC

RISK STRATAGY WITH NSAID:

RISK STRATAGY WITH NSAID IF ORAL NSAIDS ARE TAKEN FOR 2 MONTHS RISK OF ENDOSCOPIC ULCER IS 1 IN 5 SYMPTAMATIC ULCER IS 1 IN 70 BLEEDING ULCER IS 1 IN 150 DEATH FROM BLEEDING ULCER 1 IN 1300 TEXT BOOK OF PAIN,WALL&MELZACKS,CHAPTER30 SVRRGGH&SVMC

IN OUR PLACE (SVRRGGH):

IN OUR PLACE (SVRRGGH) IN A RETROSPECTIVE STUDY REASONS FOR PERITONITIS(ULCER) ARE >95% SVRRGGH&SVMC

SO……………….:

SO………………. YOU HAVE TO BE VERY CAUTIOUS WHEN USING NSAIDS DON’T USE FOR LONGER PERIODS INTENSE MONITORING IS REQUIRED ALWAYS USE IN SMALLER DOSES MULTIPLE REGIMENS WILL DECRESE THE DOSE OF DRUG & ITS SIDE EFFECTS ALWAYS USE PPI OR H1 ANTAGONISTS ALONG WITH NSAIDS USE ALTERNATIVES IF AVAILABLE SVRRGGH&SVMC

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Celecoxib [Celebrex] Rofecoxib [ Vioxx ] Valdecoxib [ Bextra ] Inhibit COX-2 more than COX-1 have been developed and approved for use. The rationale behind development of these drugs was that: inhibition of COX-2 would reduce the inflammatory response and pain not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1. COX-2 Selective agents SVRRGGH&SVMC

COX-2 Selective agents :

COX-2 Selective agents Rofecoxib and valdecoxib have been removed from the market due to a doubling in the incidence of heart attack and stroke Celecoxib remains on the market and is approved for: Osteoarthritis and rheumatoid arthritis Pain including bone pain, dental pain, and headache Ankylosing spondylitis . SVRRGGH&SVMC

COX-2 Selective agents :

COX-2 Selective agents Well tolerated compared with the NSAID regimens ( diclofenac 100 mg daily and naproxen 1000 mg daily). Successive Celecoxib Efficacy and Safety Studies (SUCCESS) showed that celecoxib was as effective as the conventional NSAIDs in controlling the pain Caused fewer GI ulcers or ulcer complications (such as perforations or bleeding) 29% less chance of having nausea 22% less chance of abdominal pain Increase risk for heart attack , thrombosis & stroke by a relative increase in thromboxane . SVRRGGH&SVMC

Paracetamol :

Paracetamol First proper account of clinical use in 1894 ( Hinsberg and Treupel ) 1 Analgesic effect formally demonstrated in 1948 ( Flinn and Brodie ) 1 Recommended first-line analgesic therapy: - for the treatment of osteoarthritis since 2000 2,3 - for musculoskeletal pain in elderly since 2002 4 - for patients with renal disease since 1996 5 1 . Prescott LF. Am J Therapeut 2000;7(2):143-7. 2. EULAR recommendations. Pendleton A et al. Ann Rheum Dis 2000;59(12):936-44. 3. American College of Rheumatology Subcommittee on osteoarthritis guidelines. Arthritis Rheum 2000;43(9):1905-15. 4. AGS Panel on Persistent Pain in Older Persons. JAGS 2002;50:S205-24. 5. Henrich WL et al. Am J Kidney Dis 1996;27(1):162-5 . SVRRGGH&SVMC

PARACETAMOL:

PARACETAMOL Central antinociceptive effect & potential mechanisms for this include inhibition of a CNS COX-2( 1,2,3 ) Inhibition of a central cyclooxygenase ‘COX-3’ that is selectively susceptible to paracetamol , Modulation of inhibitory descending serotinergic pathways-( 4,5 ) Prevent PG production at the cellular transcriptional level, independent of cyclooxygenase activity( 2,3 ) 1 . Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4. 2 . Carlsson KH et al. Pain 1988;32:313-26. 3. Flower RJ et al. Nature 1972;240:410-1. 4. Tjølsen A et al. Eur J Pharmacol 1991;193:193-201. 5 . Pélissier T et al. JPET 1996;278:8-14. SVRRGGH&SVMC

PARACETAMOL METABOLISM:

PARACETAMOL METABOLISM ( N- acetylbenzoiminoquinone ( NAPQI ) Metabolism of acetaminophen (Ac) to hepatotoxic metabolites. (GSH, glutathione; GS, glutathione moiety; Ac*, reactive intermediate.) SVRRGGH&SVMC (60%) (30%) cysteine (about 3%);

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Hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (150 to 250 mg/kg) of acetaminophen; doses of 20 to 25 g or more are potentially fatal. Conditions of CYP induction ( e.g., heavy alcohol consumption) or GSH depletion ( e.g., fasting or malnutrition) increase the susceptibility to hepatic injury, SVRRGGH&SVMC

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Hepatic safety at therapeutic doses 1 Paracetamol hepatotoxicity was found to be very rare (<1 / 2,500) 1 It was always related to misuse and overdose (>4g / day) 1 Good hepatic safety 1. Whitcomb DC et al. JAMA 1994;272(23):1845-50. SVRRGGH&SVMC

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Up to 4g / day, paracetamol has an excellent renal safety profile 1 No evidence exists for the development of chronic nephropathy with paracetamol 2 Recommended by the National Kidney Foundation as the non-narcotic analgesic of choice in patients with underlying renal disease 3 Good renal tolerance 1 . Whelton A. Am J Therapeut 2000;7(2):63-74. 2. Blantz RC. Am J Kidney Dis 1996;28(1):S3-6. 3. Henrich WL et al. Am J Kidney Dis 1996;27(1):162-5. RENAL SAFETY SVRRGGH&SVMC

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Paracetamol safety benefits in POP No centrally mediated side-effects 1 (e.g. sedation, constipation, nausea, vomiting, respiratory depression) No affect on platelet aggregation, bleeding, or uric acid excretion 2 No gastrointestinal side effects 3 Good renal 4 and hepatic 5 safety Few contra-indications and drug interactions 1. Lechat P et al. Thérapie 1989;44:337-54. 2. Insel PA. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Goodman & Gilman eds. ,The pharmacological basis of therapeutics. McGraw Hill, 9th edition, 1996:617-57. 3. Singh G. Am J Therapeut 2000;7(2):115-21. 4. Whelton A. Am J Therapeut 2000;7(2):63-74. 5. Whitcomb DC et al. JAMA 1994;272(23):1845-50. . SVRRGGH&SVMC

OPIOIDS:

OPIOIDS SVRRGGH&SVMC

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Opium is derived from the plant called Papaver Sominiferum .” In 1806, Frederich Serturner produced an opium alkaloid → self-administered → produced dreams, so he named it “ Morphine ” after Morpheus, the Greek God of dreams. SVRRGGH&SVMC

CLASSIFICATION:

CLASSIFICATION Pure agonists -Morphine -Codeine - Fentanyl - Pethidine -Methadone Pure antagonist - Naloxone - Nalmexone - Nalbuphine - Naltrexone Agonist antagonist - Morphinous - Levorphanol - Butorphanol - Benzomarphanol - Pentazocine Partial antagonist - Nallorphine Partial agonists - Thebaine - Buprenorphine SVRRGGH&SVMC

OPIOIDS ACTION :

OPIOIDS ACTION Three well-defined opioid actions: Reduce neurotransmitter release; by closing a voltage-gated Ca 2+ channel on presynaptic neuronal terminals Inhibit postsynaptic neurons (hyperpolarization) by increasing and K + channel conductance Opioids interact with other intracellular effector mechanisms, the most important being the adenylate cyclase system . SVRRGGH&SVMC

OPIOIDS:

OPIOIDS Activating opioid receptors in the midbrain & turning on the Descending inhibitory system Activating opiod receptors on the second order pain transmission cells to prevent the Ascending transmission of pain signals Activating opioid receptors at the central terminals of C fibers in the spinal cord Activating opioid receptors in the periphary to inhibit the activation of nociceptors & to inhibit cells that may release inflmmatoy mediators SVRRGGH&SVMC

Opioids- action on receptors:

Opioids - action on receptors 1: inhibit transmission of pain 2: respiratory depression, euphoria, constipation, physical dependence : inhibit transmission of pain : inhibit transmission of pain : autonomic effects, dysphoria , hallucinations Ref. 5 SVRRGGH&SVMC

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Opioid Receptor Subtype Drug Mu (m) Delta (d) Kappa (k) Opioid Peptides Enkephalins Antagonist Agonist beta-endorphin Agonist Agonist Dynorphin Weak Agonist Agonist Agonists Codeine Weak Agonist Weak Agonist etorphine Agonist Agonist Agonist fentanyl (Sublimaze) Agonist meperidine (Demerol) Agonist methadone (Dolophine) Agonist Morphine Agonist Weak Agonist Agonist-antagonists Buprenorphine Partial Agonist dezocine (Dalgan) Partial Agonist Agonist nalbuphine (Nubain) Antagonist Agonist pentazocine (Talwain) Antagonist or Partial Agonist Agonist Antagonist : naloxone (Narcan) Antagonist Antagonist Antagonist SVRRGGH&SVMC

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Morphine Actions- CNS : Cortical areas – supraspinal analgesia tolerance physical dependance addiction muscle rigidity & tone convulsions Diencephalon/ Mesencephalon – Upper Pons c) Medulla/Floor of IV Ventricle SVRRGGH&SVMC

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Cortical areas Supraspinal Analgesia — Strong analgesic Dull continuous pain is relieved more effectively than sharp shooting pain. Action on Cingulate gyrus , parahippocampal region & limbic system – Mood changes, euphoria, tranquility, mental clouding, drowsiness, indifference to surroundings as well as to our body . SVRRGGH&SVMC

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Repeated opioid administration results in a gradual loss of effect or when more drug is required to produce a desired effect. Tolerance is not developed equally to all opioid effects Tolerance is mainly due to receptor desensitisation induced by functional uncoupling of opioid receptors from G-proteins, thus uncoupling the receptors from their effector systems. 2) Tolerance SVRRGGH&SVMC

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Opioid Effects: Degree of Tolerance Developed 2) Tolerance SVRRGGH&SVMC High Intermediate Limited/None analgesia bradycardia miosis euphoria, dysphoria constipation mental clouding convulsions sedation antagonist actions respiratory depression antidiuresis nausea/vomiting cough suppression

Drug dependence:

Drug dependence A cluster of physiological, behavioural and cognitive phenomena of variable intensity, in which the use of a psychoactive drug (or drugs) takes on a high priority--1964 the WHO Expert Committee A strong desire or sense of compulsion to take the drug; Difficulties in controlling drug-taking behaviour in terms of its onset, termination, or levels of use; A physiological withdrawal state when drug use is stopped or reduced, as evidenced by: the characteristic withdrawal syndrome for the substance; or use of the same (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms; Evidence of tolerance, such that increased doses of the drug are required in order to achieve effects originally produced by lower doses; Progressive neglect of alternative pleasures or interests because of drug use, increased amount of time necessary to obtain or take the drug or to recover from its effects; Persisting with drug use despite clear evidence of overtly harmful consequences, such as harm to the liver, depressive mood states or impairment of cognitive functioning WHO and DSM-IV-TR SVRRGGH&SVMC

Pharmacokinetics of Routes:

Pharmacokinetics of Routes SVRRGGH&SVMC

OPIOID DEPENDENCE:

OPIOID DEPENDENCE Physical Psychological dependence dependence (withdrawal symptoms) (addiction) Diarrhoea , palpitation Craving and sweating unsanctioned dose loss of other interests SVRRGGH&SVMC

Physical Dependence:

Physical Dependence Physical Dependence —physiological withdrawal of symptoms(abstinence syndrome) if antagonist is administered or agonist is stopped Adenylate cyclase (AC) has long been implicated in opioid withdrawal Increased AC activity following chronic morphine treatment has been observed in the locus ceruleus , which is considered to play a major role in opioid withdrawal. Features of withdrawal syndrome on stoppage of opioid . -- Restlessness, yawning, sweating, lacrimation , running nose, tachycardia, abdominal cramps, nausea, vomiting . SVRRGGH&SVMC

Addiction(psychalogical dependence):

Addiction( psychalogical dependence) A compulsive preoccupation with and continued use of an agent despite no benefit and often in the face of harmful effects. A pattern of compulsive drug use characterized by continued craving for an opioid and the need to use the opioid for effects other than pain relief. Dysphoria Malaise Cravings Anxiety / Panic Attacks Paranoia Insomnia Dizziness Nausea Depression SVRRGGH&SVMC

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(5) Increased muscular rigidity & tone - Fentanyl : due to effect on dopaminergic transmission in striatum of basal ganglia ( extrapyramidal system) (6) Convulsion – High doses µ and δ receptor - due to inhibition of release of GABA by interneurons Leads to excitation of Neurons SVRRGGH&SVMC

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Diencephalon, Mesencephalon – upper pons Modulation of pain Fall in body temperature Edinger-Westphal Nucleus – Occulomotor nucleus is stimulated  Stimulation of sphinctor pupillae  Miosis . Opioid toxicity – Pinpoint pupil. SVRRGGH&SVMC

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Medulla/Floor of IV Ventricle – Respiratory depression- Dose dependent respiratory depression. ↓ Respiratory rate & Tidal volume. Reduction in responsiveness of brainstem respiratory centres to increase in PaCO 2 Death in opioid poisoning is always due to respiratory arrest. SVRRGGH&SVMC

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Apneustic breathing – Initially increased Tidal Volume leading to deep, slow sighing type of 4-6 breaths/min. If the patient is consciousness & stimulated then the breathing will continue. (B) Cough : Cough centre is depressed Antitussive action Codeine (C) Nausea & Vomiting – Stimulation of Chemoreceptor trigger zone(CTZ) (D) Bradycardia – By Fentanyl Stimulation of vagal centre. Blocked by Atropine. SVRRGGH&SVMC

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( H) Biliary System – Spasm of sphincter of oddi ↓ Biliary Spasm,Cholesystic Jaundice Urinary Bladder & Ureter – Causes urinary retention by Detrusor relaxation & Sphincteral spasm . (J) Skin – Pruritis Sensation of Itching in nose Flushing of skin of head, neck & face SVRRGGH&SVMC

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Pharmacokinetics Absorption and distribution – Readily absorbed from GIT. Route of administration is i.v.,i.m . Highly lipid soluble. SVRRGGH&SVMC

Opioid Pharmacology:

Opioid Pharmacology Opioids reach their peak plasma concentration approximately 60 to 90 minutes after oral or rectal administration 30 minutes after subQ or IM injection 6 minutes after intravenous administration When renal clearance is normal, hydrocodone , hydromorphone , morphine, oxycodone , and their metabolites all have effective half-lives of about 3-4 hours. When dosed repeatedly, their plasma concentrations approach a steady-state after 4 to 5 half lives. SVRRGGH&SVMC

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Metabolism Morphine undergoes hepatic glucoronidation to Morphine-6-glucoronide & Morphine-3-glucoronide. Morphine-6-glucoronide- Active metabolite - Responsible for Analgesia Both are excreted through kidney . SVRRGGH&SVMC

Oral Morphine :

Oral Morphine How to use Start with 5 - 10mg i /r MST Always use q4h with double dose at bed time Additional doses can be given p.r.n . for breakthrough pain If pain relief is not satisfactory, increase by approximately 50% of previous dose SVRRGGH&SVMC

Breakthrough dosing :

Breakthrough dosing When flares of pain last for more than few minutes, extra doses of analgesics may be helpful For each breakthrough dose, offer 5% to 15% of the 24-hour dose A breakthrough dose can be offered once Cmax has been reached SVRRGGH&SVMC

Oral Morphine :

Oral Morphine How to use There is no maximum dose of morphine; the dose can be increased depending on the severity of pain “Pain is the physiological antagonist to the central side effects of morphine.” SVRRGGH&SVMC

Oral Morphine :

Oral Morphine How to use Always prescribe a laxative (stimulant +/- softener) prophylactically “The hand that prescribes the Morphine should also writes laxatives” Prescribe an anti-emetic prophylactically for the first few days , especially in patients who are already vomiting SVRRGGH&SVMC

Exceptions to ‘every four hours’:

Exceptions to ‘every four hours’ Renal failure Very elderly > 70 yrs increase dosing interval decrease dosage size Accumulation of M6G leads to enhanced opioid toxicity. Oral Morphine SVRRGGH&SVMC

Misunderstandings about morphine:

Misunderstandings about morphine ‘Morphine is dangerous because it depresses respiration ’ Double dose at bed time does’nt cause RD Large therapeutic window Drowsiness and delirium prevents from taking further dose Tolerance to respiratory depression develops in course of time SVRRGGH&SVMC

Misunderstandings about morphine:

Misunderstandings about morphine ‘Morphine is addictive ’ Several studies have concluded that risk of addiction is far less than 1% Two studies with more than 500 patients who received Heroin for pain relief found that no patient could be documented as having become addicted Twycross , 1974; Twycross , Wald, 1976 Prospective study of 11,882 hospitalised medical patients only 4 patients could be documented as having become addicted as a result of receiving opioid analgesics Porter, Jick , 1980 SVRRGGH&SVMC

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Oral Morphine Results of 2 year study in India SVRRGGH&SVMC

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Fentanyl Synthetic opioid. 80 times more potent than Morphine. Metabolised to Nor Fentanyl in liver. Excreted in urine & bile. Suitable for patients in Renal failure. i.v ., subcutaneous, transdermal , transmucosal , Neuraxial administration. Transdermal administration of Fentanyl using iontophoresis ( Ionsys TM ,Janssen-Cilag Ltd.) is a novel on-demand drug delivery system. SVRRGGH&SVMC

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It differs from Morphine – very highly lipid soluble - rapid onset & recovery. due to rapid distribution in fat & muscles-Rapidly crosses Blood Brain Barrier. devoid of cardiac effects. may produce Bradycardia . SVRRGGH&SVMC

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Meperidine ( Pethidine ) Synthetic opioid. Biotransformed by liver to Normeperidine , it is potentially neurotoxic metabolite. Half life is 12-16 hr. Repetetive dosing causes accumulation of normeperidine which precipitate tremulousness, myoclonus & Seizures . Contraindicated in patients receiving Monoamine oxidase inhibitors as it precipitate a syndrome characterised by muscle rigidity,hyperpyrexia & Seizures. SVRRGGH&SVMC

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Partial Agonist  Buprenorphine – Potent semisynthetic opioid. Not related to Morphine but to Thebaine . 50 times greater affinity than that of Morphine. Respiratory depression is prolonged. Naloxone cannot reverse its actions. CNS stimulant like doxapram is needed. Indicated in cancer pain. SVRRGGH&SVMC

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Agonist – Antagonist Agonist at one receptor & antagonist at another. Pentazocine  κ 1 agonist. Produces Spinal level analgesics. Sedation, drowsiness & respiratory depression. Due to σ stimulation it causes – Dysphoria , hallucinations, diaphoresis & psychotomimetic effects.(active thoughts, depersonalization, feeling of impending doom.) SVRRGGH&SVMC

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Increases blood pressure Increases heart rate Increases pulmonary artery pressure. Indicated in post operative pain, moderately severe pain in burns, trauma, fractures etc . SVRRGGH&SVMC

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Butorphanol 20 times more potent than pentazocine . Minimal σ effect. Less respiratory depression. Drug of choice in acute pain, post-operative pain. Neither substitute for, nor antagonize Morphine. Very weak interaction with µ receptors . Dose → 1-4 mg i.m . or i.v . SVRRGGH&SVMC

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Pure Antagonist – Naloxane — Completely reverses the actions of all pure, partial, agonist-antagonist at µ, κ , σ , δ and including analgesia, respiratory depression. Causes -Nausea & Vomiting. -Tachycardia -Hypertension -Pulmonary oedema -Cardiac Arrythmias Dose → 0.4 mg/ml – loading dose Repeated after 5 min - 50µg. SVRRGGH&SVMC

TRAMODOL:

TRAMODOL Opioid analgesic due to its weak binding of OP1,OP2,OP3 receptors Inhibits norepinephrine and serotonin uptake Both non-opioid and opioid mechanisms contribute to the antinociceptive effects of tramadol NO RESPIRATORY DEPRESSION sedation, nausea and constipation SVRRGGH&SVMC

TAPENTADOL:

TAPENTADOL Centrally acting analgesic with a unique dual mode of action as an agonist at the μ-opioid receptor & as a norepinephrine reuptake inhibitor 18-fold affinity for the μ opioid receptor in as compared to morphine Improved GI tolerability when compared to opioids Dose adjustment is not needed in the presence of renal impairment No Hepatoxicity Potency between Tramadol and Morphine Contraindicated in severe bronchial asthma, paralytic ileus , and patients on MAOI SVRRGGH&SVMC

Adjuvant Pain Medications:

Adjuvant Pain Medications “drugs that are used primarily for treating conditions other than pain, but may be analgesic in selected circumstances” -AMA SVRRGGH&SVMC

Common Adjuvant Medications:

Common Adjuvant Medications Antidepressants Anticonvulsants Corticosteroids Topical Anesthetics Calcitonin Bisphosphonates SVRRGGH&SVMC

STEROIDS:

STEROIDS ACTION - MEMBRANE STABILISATION, BLOCKADE OF PHOSPHOLIPASE-2 ACTIVITY, PROLONGED SUPPRESSION OF ONGOING NEURONAL DISCHARGE, SUPPRESSION OF SENSITISATION OF DORSAL HORN NEURONS, ANTIOEDEMA ACTIVITY SIDE EFFECTS SUPPRESSION OF HPA AXIS,PEPTIC ULCER DISEASE,OSTEOPOROSIS,SKELETAL MUSCLE MYOPATHY etc COMMANLY USED ARE DEXAMETHASONE,TRIAMCINALONE,METHYLPREDNISOLONE SVRRGGH&SVMC

CHRONIC PAIN / NEUROPATHIC PAIN:

CHRONIC PAIN / NEUROPATHIC PAIN SVRRGGH&SVMC

PATHOLOGICAL CHANGES--SITES:

PATHOLOGICAL CHANGES--SITES HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG DRG INJURY C FIBRE A β GLUTAMATE PEPTIDES SP PHENOTYPIC CHANGES PHENOTYPIC CHANGES MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE AP DP ALTERATION OF INHIBITORY CONTROLE ECTOPIC CHANGES ECTOPIC CHANGES SVRRGGH&SVMC

EFFECTS OF PATHOGENESIS:

EFFECTS OF PATHOGENESIS HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG CENTRAL SENSITIZATION GENE REGULATION MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE INHIBITION OF TRANSMISSION ALTERATION OF INHIBITORY CONTROLE EXCITABILITY DESENSITIZATION SVRRGGH&SVMC

CURRENT THEARUPATIC TARGETS:

CURRENT THEARUPATIC TARGETS HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG CENTRAL SENSITIZATION GENE REGULATION MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE ALTERATION OF INHIBITORY CONTROLE EXCITABILITY DESENSITIZATION INHIBITION OF TRANSMISSION TCA Na .C.B.-LIDOCAINE CAPSAICIN α 2 d agonist GABA,PREGB α 2 d agonist GABA,PREGB ANTIDEPRESSENTS OPIOIDS NEUROSTIMULATION FLUPERITINE OPIOIDS ????? ????? SVRRGGH&SVMC

THERAPIES ACTING ON NEW TARGETS FOR NP:

THERAPIES ACTING ON NEW TARGETS FOR NP HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG CENTRAL SENSITIZATION GENE REGULATION MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE INHIBITION OF TRANSMISSION ALTERATION OF INHIBITORY CONTROLE EXCITABILITY DESENSITIZATION NEUOTROPHINS GDNF,ANTI NGF Na Channel Blockers POTASSIUM OPENERS TRPV1 agonist/antagonist AMPA antagonists mGalutamate inhibitors Dextrometorphin Quinidine Ca channel blockers Novel α 2 d agonist CCL2 INHIBITORS MAPK INHIBITORS GABA AGONISTS CANNBINOID RECEPTOR AGONISTS 5HT 17 AGONISTS ADENOSNE SVRRGGH&SVMC

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Step 1 Step 2 Step 3 Step 4 Step 5 Coticosteroid For Nerve Compression Opioids Tricyclic antidepressant or anti-epileptic Tricyclic anti depressant and anti-epileptic NMDA -receptor -channel blocker Invasive Techniques Treatment of NeuropathicPain -CANCER SVRRGGH&SVMC

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SVRRGGH&SVMC

TRYCYCLIC ANTIDEPRESSANTS:

TRYCYCLIC ANTIDEPRESSANTS Amitryptiline : Particularly in burning type of pain Action : Prevention of reuptake of serotonin& Norad Alfa adrenergic blockade Na channel effect, NMDA antagonism Start with 10 to 25 mg at night and increase every third day up to 75 to 100 mg if necessary Side effects - sedation, constipation, urinary retention, heart block aggravated Other TCAs - SVRRGGH&SVMC

SECONDARY AMINES TCAs Nortriptyline,desipramine :

SECONDARY AMINES TCAs Nortriptyline,desipramine Starting dosage 25 mg at bedtime Titration Increase by 25 mg daily every 3–7 days as tolerated Maximum dosage 150 mg daily; if blood level of active medication and its metabolite is below 100 ng /ml (mg/ml), continue titration with caution Therapeutic index + Duration of adequate trial 6–8 weeks with at least 2 weeks at Maximum tolerated dosage Major side effects Sedation, dry mouth,blurred vision,weight gain,urinary retention Precautions Cardiac disease,glaucoma , suicide risk, seizure disorder, concomitant useof tramadol Other benefits Improvement of depression,improvement of insomnia SVRRGGH&SVMC

SNRIs -Duloxetine :

SNRIs - Duloxetine Starting dosage 30 mg once daily Titration Increase to 60 mg once daily after one week Maximum dosage 60 mg twice daily Therapeutic index ++ Duration of adequate trial 4 weeks Major side effects Nausea Precautions Hepatic dysfunction,renal insufficiency,alcohol abuse, concomitant use of tramadol Other benefits Improvement of depression SVRRGGH&SVMC

SNRIs- Venlafaxine :

SNRIs- Venlafaxine Starting dosage 37.5 mg once or twice daily Titration Increase by 75 mg each week Maximum dosage 225 mg daily Therapeutic index + Duration of adequate trial 4–6 weeks Major side effects Nausea Precautions Concomitant useof tramadol, cardiac disease, withdrawal syndrome with abrupt discontinuation Other benefits Improvement of depression SVRRGGH&SVMC

Calcium channel a2-d ligands:

Calcium channel a2-d ligands ACTION- Modulate the cellular Ca influx into nociceptive neurons by binding to vlotage gated Ca channels Preferred in Post Herpetic Neuralgia & Diabetic neuropathy Less side effects Expensive GABAPENTIN &PREGABALIN SVRRGGH&SVMC

Calcium channel a2-d ligands Gabapentin :

Calcium channel a2-d ligands Gabapentin Starting dosage 100–300 mg at bedtime or 100–300 mg three times daily Titration Increase by 100–300 mg three times daily every 1–7 days as tolerated Maximum dosage 3600 mg daily (1200 mg three times daily); reduce if impaired renal function Therapeutic index ++ Duration of adequate trial 3–8 weeks for titration plus 2 weeks at maximum dosage Major side effects Sedation, dizziness, peripheral edema Precautions Renal insufficiency Other benefits Improvement of sleep disturbance, no clinically significant drug interactions SVRRGGH&SVMC

Calcium channel a2-d ligands Pregabalin :

Calcium channel a2-d ligands Pregabalin Starting dosage 50 mg tid or 75 mg bid Titration Increase to 300 mg daily after 3–7 days, then by 150 mg/d every 3–7 days as tolerated Maximum dosage 600 mg daily (200 mg tid or 300 mg bid); reduce if impaired renal function Therapeutic index ++ Duration of adequate trial 4 weeks Major side effects Sedation, dizziness, peripheral edema Precautions Renal insufficiency Other benefits Improvement of sleep disturbance, improvement of anxiety,no clinically significant drug interactions SVRRGGH&SVMC

LIDOCAINE PATCH 5%:

LIDOCAINE PATCH 5% LIDOCAINE 5% IN PLIABLE PATCH UP TO 3 PATCHES APPLIED ONCE DAILY OVER PAINFULL SITE -12H ON,12H OFF(FDA APPROVED LABEL) -RECENTLY PUBLISHED DATA INDICATE 4 PATCHES(18-24H) SAFE EFFICASY DEMONSTRATED IN 3 RCT ON PHN DRUG INTERACTIONS AND SYSTEMIC SIDE EFEECTS UNLIKELY—MOST COMMON SIDE EFFECT –APPLICATION SITE SENSITIVITY CLINICALLY INSIGNIFICANT SEERUM LIDOCAINEW LEVELS MECHANICAL BARRIER DECREASES ALLODYNIA SVRRGGH&SVMC

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Topical lidocaine -5% lidocaine patch :

Topical lidocaine -5% lidocaine patch Starting dosage Maximum of 3 patches daily for a maximum of 12 h Titration None needed Maximum dosage Maximum of 3 patches daily for a maximum of 12–18 Therapeutic index ++ Duration of adequate trial 3 weeks Major side effects Local erythema, rash Precautions None Other benefits No systemic side effects SVRRGGH&SVMC

OPIOIDS –NEUROPATHIC PAIN:

OPIOIDS –NEUROPATHIC PAIN First-line medications only in certain clinical circumstances, ie , Acute neuropathic pain, Neuropathic cancer pain, Episodic exacerbations of severe neuropathic pain, or When titrating one of the first-line medications if prompt painrelief is required SVRRGGH&SVMC

NONPHARMACOLOGICAL MANAGEMENT OF PAIN:

NONPHARMACOLOGICAL MANAGEMENT OF PAIN

NONPHARMACOLOGICAL MANAGEMENT:

NONPHARMACOLOGICAL MANAGEMENT Increase the individual control feeling. Decrease the feeling of weakness. Improves the activity level and functional capacity. Reduces stress and anxiety. Reduces the pain behavior and focused pain level. Reduces the needed dosage of analgesic drugs thus decreasing the side effects of the treatment ( Yıldırım 2006). ( Delaune & Ladner 2002). SVRRGGH&SVMC

NONPHARMACOLOGICAL MANAGEMENT:

NONPHARMACOLOGICAL MANAGEMENT In a study with 31.044 adults in United States, determined that the usage rate of the complementary methods for the last year has been 36% and back pain and lumbago come first with 16.8% and neck pain comes third with 6.6% in terms of usage reasons of the complementary methods .( Barneset al. (2004) 24% of the patients with chronic lumbago used massage therapy(Sherman et al. (2004) NONPHARMACOLOGICAL therapies can be useful in pain management ( Uçan and Ovayolu2007). SVRRGGH&SVMC

NONPHARMACOLOGICAL MANAGEMENT:

NONPHARMACOLOGICAL MANAGEMENT Peripheral therapies (physical agents/skin stimulation methods), Cognitive-behavioral therapies and Other therapies ( Turan et al. 2010). Non-pharmacological therapies aim to treat the affective, cognitive, behavioral and socio-cultural dimensions of the pain ( Yavuz 2006) SVRRGGH&SVMC

Peripheral therapies (physical agents/skin stimulation):

Peripheral therapies (physical agents/skin stimulation) TENS ( Transcutaneous Electrical Nerve Stimulation) Hot-cold treatment Acupuncture and acupressure- Gate Control Theory Raising Pain Threshold Theory Exercise Positioning Restriction of movement /resting Massage- friction, percussion, vibration and tapotement ) Hydrotherapy ( Balneotherapy ) These methods are effective on secondary pathologies such as inflammation, edema, progressive tissue damage, muscle spasm and function loss which takes part in acute pain. ( Yıldırım 2006). SVRRGGH&SVMC

Cognitive-behavioral therapies:

Cognitive-behavioral therapies Relaxation - respiration techniques and dreaming The sensitivity developed against the pain should be prevented by means of these techniques ( Karagöz , 2006). Distraction- Getting the attention away from the pain reduces its severity Method includes listening to music, watching television, reading books and dreaming ( Arslan & Çelebioğlu , 2004). SVRRGGH&SVMC

Cognitive-behavioral therapies:

Cognitive-behavioral therapies Praying- Praying method in order to reduce the depression and anxiety that is caused by chronic pain ( Meisenhelder & Chandler, 2000; Karagöz , 2006 ). Meditation - Meditation helps relaxation, it is thought to be effective in relieving the pain (Gray,2004). Carson et al (2005) have stated that an 8-week meditation is useful for relieving the pain for patients with chronic lumbago. SVRRGGH&SVMC

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Yoga Yoga is providing relaxation by using respiration exercises and meditation with slowmovements Study that applying yoga for 16 weeks has cured the chronic lumbago (Williams et al. 2005) Functional insufficiency experienced with chronic lumbago and use of pain killers have been reduced by means of yoga.(Williams et al -2005) SVRRGGH&SVMC

Cognitive-behavioral therapies:

Cognitive-behavioral therapies Hypnosis “ the deep physical relaxation state during which subconscious can be reached and important abilities are suspended” Jensens and Patterson (2006) - hypnotherapy/hypnosis is used for analgesia in various types of chronic pains and it has been stated that hypnosis has been effective for neck pain. Liossi et al (2006) has made a study with pediatric cancer patients in which it has been determined that hypnosis application has decreased pain and anxiety level in patients SVRRGGH&SVMC

Cognitive-behavioral therapies:

Cognitive-behavioral therapies Bio-feedback Biofeedback appliers train the patient in terms of mental and physical exercises, visualization and deep breaths ( Eidelson,2005) In many types of chronic pain the bio-feedback has been shown to be effective (Moseikin 2003; Teyhen et al. 2005 SVRRGGH&SVMC

Cognitive-behavioral therapies:

Cognitive-behavioral therapies Behavioral therapy Aim of this therapy is to increase the functional level of the patient decrease the maladaptive behaviors and firstly reduce and then completely stop painkiller usage The family is trained by the treatment team; Description of pain (grimacing, moaning, and remaining motionless)is avoided and well-adaptive behaviors such as physical activities are reinforced ( Brietbartet al. 2004). SVRRGGH&SVMC

Other non-pharmacological therapies:

Other non-pharmacological therapies Reflexology Herbal treatments Aromatherapy Chiropractics Musical therapy SVRRGGH&SVMC

Advantages and Disadvantages of Some Non-pharmacological Methods:

Advantages and Disadvantages of Some Non-pharmacological Methods Attempt Advantage Disadvantage Relaxation Bio-feedback Distraction It may reduce the pain and anxiety without having drug-related side effects. It can be used more likely as an adjuvant therapy together with other methods. It may increase the management feeling of the patient. Most of them are not expensive, they do not require special equipment and they are easily applicable The patients should be aware of using the management strategies by theirselves . An appropriate time zone is needed to teach the attempts Psychotherapy, Hypnosis It may reduce the pain and anxiety of the patients who have pains that are relatively difficult to manage.  It may increase the number of methods that the patient uses to manage. It requires an experienced therapist SVRRGGH&SVMC

Advantages and Disadvantages of Some Non-pharmacological Methods:

Advantages and Disadvantages of Some Non-pharmacological Methods Attempt Advantage Disadvantage Skin Stimulation/ Cutane ous Stimulation (superficial hot-cold application and massage) It may reduce muscle spasms, inflammation and pain. It can be used more likely as an adjuvant therapy together with other methods. It may increase the controlling ability of pain feeling of the patient. It is so easy to use. It may be applied by the patients or families. It is a cheap method Hot application can increase the bleeding or edema after acute injuries. Cold application is contraindicate for the situations such as uritcaria /hypersensitivity, hypertension, Reynaud's phenomenon and sickle cell anemia which are related to cold. Transcutaneous Electrical Nerve Stimulation (TENS It reduces the pain without having any drug-related side effects. It can be used more likely as an adjuvant therapy together with other methods. It gives the feeling of pain management to the patient It requires an experienced therapist. There is a risk for bleeding and infection. There are no reliable results for use in cases of pregnant women. SVRRGGH&SVMC

Advantages and Disadvantages of Some Non-pharmacological Methods:

Advantages and Disadvantages of Some Non-pharmacological Methods Attempt Advantage Disadvantage Aromatherapy It has an analgesic effect. It has a sedative and relaxing effect It may cause hypersomnia . Some herbs should not be used with other antidepressants and alcohol. Acupuncture It may provide pain reduction without any side effects. It can be used more likely as an adjuvant therapy together with other methods. It requires an experienced therapist SVRRGGH&SVMC

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