This document discusses pain and its treatment. It begins by defining pain and classifying common types of pain conditions. It then discusses the body's reflex responses to pain and the endorphin system that modulates pain. It describes the differences between acute and chronic pain and methods of pain measurement. Various treatment options are provided for different types of pain, including NSAIDs, opioids, tramadol, tapentadol, muscle relaxants, and sodium channel blockers. Newer treatments discussed include epirisone and the comparative properties of different NSAIDs, muscle relaxants, tramadol, and tapentadol. Key questions are also provided about comparing treatment effectiveness and safety across patient subgroups.

1. PAIN

2. DefinitionAn unpleasant sensory and emotional experience arising from actual or potential tissue damage--The International Association for the Study of Pain

3. CLASSIFICATION AND PREVALENCE OF COMMON PAIN CONDITIONS

5. Reflex responses to painIncreased Sympathetic ToneVasoconstriction producing increased peripheral resistance

6. Increased cardiac output from increased stroke volume

7. and heart rate

8. Increased blood pressure

9. Increased metabolic rate and oxygen consumption

10. Decreased gastric tone (delayed gastric emptying; can

11. progress to ileus)

12. Decreased urinary tract tone (leads to urinary retention)Endocrine ResponsesDecreased insulin production

13. Increased cortisol

14. Increased antidiuretic hormone

15. Increased growth hormone

16. Increased renin, angiotensin II, aldosterone

17. Increased glucagons

18. Increased catecholaminesRespiratory ResponsesHyperventilationCortical ResponsesAnxiety and fearEndorphin SystemNeuroendocrine system that serves to modulate responses to pain and stress

19. Acute versus Chronic Pain

20. Pain Measurement

21. Sites for pain treatment

22. TreatmentFour main treatment groups:Acute pain, Chronic painRecurrent pain, and Chronic pain of malignancy.

23. TreatmentChronic painPatients should be using acetaminophen if not contraindicated andAn nonsteroidal anti-infammatory drug (NSAID) if it can be tolerated. Tramadol may be helpful in certain cases.Adjuvants appropriate for neuropathic or central pain may be added if appropriate. Opioids should not be prescribed until these other treatments are maximized and should be added in addition to these other therapies rather than as an alternative

24. Treatment of chronic Non cancer painEuropean Journal of Neurology 2010, 17: 1113–1123Institute for Clinical Systems Improvement, Assessment and Management of Chronic Pain, Fourth Edition/November 2009

26. Treatment of chronic Cancer painINCIDENCE OF PAINOver 80% of cancer patients with advanced metastatic disease suffer pain Pain is caused mostly by direct tumor infiltration. Pain undermines quality of life considerably and is a clinically important indicator of tumor progression.

27. Treatment of chronic Cancer painTreatment of mild pain (NRS: 1–4) (WHO step I analgesics)Annals of Oncology 20 (Supplement 4): iv170–iv173, 2009

28. Selected non-opioid analgesics (WHO step I)Note : internationally no NSAID is available in injectable form, hence this group is never used for acute post operative pain not because they are not effective but because pts may not have been put on oral medicines or oral diet.Annals of Oncology 20 (Supplement 4): iv170–iv173, 2009

29. Treatment of chronic Cancer painTreatment of moderate pain (NRS: 5–7) (WHO step II analgesics)The doses of these combination products can be increased until their maximum dose is attained (e.g. 4000 mg of acetaminophen and 240 mg of codeine)Annals of Oncology 20 (Supplement 4): iv170–iv173, 2009

30. selected Opioids for mild to moderate pain (WHO level II)Again TRAMADOL is also not very commonly available as injectionAnnals of Oncology 20 (Supplement 4): iv170–iv173, 2009

31. Treatment of chronic Cancer painTreatment of Severe pain (NRS: 8–10) (WHO step III analgesics)Annals of Oncology 20 (Supplement 4): iv170–iv173, 2009

32. Opioids for moderate to severe pain (WHO step III: may be combined with step I medication)a- The relative effectiveness varies considerably in published literature and between individual patients. Switching to another opiod should therefore be donecautiously with a dose reduction of the newly prescribed opioid.b - The maximal dose depends on tachyphylaxis.c - Calculated with conversion from mg/day to lg/h.d - Not usually used as firstopioid (the 12 lg/h dose corresponds to 30–60 mg of oral morphine sulfate daily).e - Factor 4 for daily morphine doses <90 mg, factor 8 for doses 90–300 mg and 12 for >300 mg.Annals of Oncology 20 (Supplement 4): iv170–iv173, 2009

33. Non-steroidal anti-inflammatory drugNSAIDs

34. Application of NSAIDsRheumatoid arthritisOsteoarthritisInflammatory arthropathies (e.g. ankylosingspondylitis, psoriatic arthritis, Reiter's syndrome)Acute goutDysmenorrhoea (menstrual pain)Metastatic bone painHeadache and migrainePostoperative painMild-to-moderate pain due to inflammation and tissue injuryPyrexia (fever)IleusRenal colicThey are also given to neonate infants whose ductusarteriosus is not closed within 24 hours of birthPrevention of colorectal cancer.Treatment of cancer and cardiovascular disease.

35. ClassificationSalicylatesAspirin (acetylsalicylic acid)DiflunisalSalsalateFenamic acid derivativesMefenamic acidMeclofenamic acidFlufenamic acidTolfenamic acidPropionic acid derivativesIbuprofenNaproxenFenoprofenKetoprofenFlurbiprofenOxaprozinLoxoprofenAcetic acid derivativesIndomethacinSulindacEtodolacKetorolacDiclofenac (Safety alert by FDA)NabumetoneEnolic acid derivativesPiroxicamMeloxicamTenoxicamDroxicamLornoxicamIsoxicam

36. ClassificationSelective COX-2 inhibitors (Coxibs)Celecoxib (FDA alert)1Rofecoxib (withdrawn from market)Valdecoxib (withdrawn from market)Parecoxib FDA withdrawn, licenced in the EUEtoricoxib FDA withdrawn, licenced in the EUFirocoxib used in dogs and horsesSulphonanilidesNimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity)OthersLicofelone acts by inhibiting LOX & COX and hence known as 5-LOX/COX inhibitorhttp://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvid

37. Differences between different NSAIDsThere is little difference in clinical efficacy among the NSAIDs when used at equivalent doses1Differences present are with regards to Dosing regimens (related to the compound's elimination half-life), Route of administration, and Tolerability profileRegarding adverse effectsselective COX-2 inhibitors have lower risk of gastrointestinal bleeding, but a substantially more increased risk of myocardial infarction than the increased risk from nonselective inhibitors.[1]partially selective nabumetone is less likely to cause gastrointestinal events.[1] The nonselective naproxen appears to be risk-neutral with regard to cardiovascular events.[1]Comparing NSAIDs - Summaries of key questions from the Drug Effectiveness Review Project (DERP), Oregon Health & Science University. By Laura Dean, National Center of Biotechnology Information (NCBI)

38. Patients at increased risk for NSAID GI toxicity1High riskHistory of a previously complicated ulcer, especially recent Multiple (>2) risk factors Moderate risk (1 – 2 risk factors)Age >65 years High dose NSAID therapy A previous history of uncomplicated ulcer Concurrent use of aspirin (including low dose), corticosteroids or anticoagulantsLow riskNo risk factorsH. pylori It is an independent and additive risk factor and needs to be addressed separately (see text and recommendations). ACG practice guidelines, Am J gastroenterol 2009; 104:728 – 738

39. Recommendations for prevention of NSAID-related ulcer complications1 ACG practice guidelines, Am J gastroenterol 2009; 104:728 – 738

40. Some Questions that need to be answered regarding NSAIDsQuestion 1Are there differences in effectiveness between NSAIDs?Question 2 & 3Are there clinically important differences in short-term (< 6 months) or long-term (≥ 6 months) harms between NSAIDs?Question 4Are there subgroups of patients based on demographics, other medications (e.g., aspirin), socio-economic conditions, co-morbidities (e.g., gastrointestinal disease) for which one medication is more effective or associated with fewer harms?These questions are answered in the document provided.

41. Tramadol & TapentadolDual Analgesic Mechanisms

42. TramadolOpioid ActivityTramadol produces antinociception via predominantly, a mu-opioid receptor mechanism.No respiratory depression, sedation, or constipation, as observed with other opiates.No analgesic toleranceNo psychological dependence or euphoric effects in long-term clinical trialsMonoaminergic ActivityNoradrenergic and serotonergic neurons originate in the brainstem and terminate in the dorsal horn of the spinal cordMonoaminergic pathway modulates the spinal processing of nociception through the section of norepinephrine and serotoninTramadol’s novel mechanism of analgesic action is partially due to its adrenergic action and Enhanced secretion of serotonin and inhibits the reuptake of serotonin in the CNS by tramadol.

43. TramadolCYP2D6 PathwayTramadol is a racemic mixture of a (+)- and a (-)-enantiomer.+ enantiomer is selective agonist of mu-opiate receptors and preferentially inhibits serotonin reuptake.-veenantiomer mainly inhibits noradrenaline reuptakeTramadol is a prodrug that requires transformation by the cytochrome P450 complex to the metabolically active O-desmethyl-tramadol.The parent molecule also produced analgesia via a monoaminergic action

44. TramadolEfficacyEffective and well-tolerated analgesic in all 3 forms of administration.(PO,IV,PR)Onset of analgesia is within 30 minutesDuration of action from 3 to 7 hoursDrowsiness is the most frequent side effectNo adverse effects were observed in the parturient after labor or in the newborn when given for Labour pain relief

45. TramadolRoutes of adminsitrationPOIVPRIntra-thecalEpidural

46. TramadolAdverse EventsDependenceWithdrawal symptoms after abrupt discontinuation or reduction of dose.hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and unusual sensory experiences can occur in rare casesSerotonin SyndromeMinor possibility of this exists with both tramadol and tapentadolAvoid concurrent administration of SSRI’s or selective-norepinephrine reuptake inhibitors, triptans, or tricyclic antidepressants

47. Tapentadol FDA approved tapentadol hydrochloride in 2008for oral treatment of moderate-to-severe acute pain in patients older than 18 yearsCentrally acting analgesic with 2 mechanisms of action in a single molecule: mu-opioidagonism and norepinephrine reuptake inhibition

48. Major DifferenceTapentadol is as effective as oxycodone or morphine, with a lower incidence of gastrointestinal adverse side effects

49. TapentadolPharmacokineticsOral absorption of tapentadol is rapidIs present in the serum in the form of conjugated metabolitesExcretion was exclusively renal (99%: 69% conjugates; 27% other metabolites; 3% in unchanged form)

50. Skeletal Muscle RelaxantsUse to treat 2 different types of conditionsSpasticityMuscular pain or spasmsupper motor neuron syndromesperipheral musculoskeletal conditionsAssociated with exaggerated cutaneous reflexes, autonomic hyper-reflexia, dystonia,contractures, paresis, and fatigabilityFibromyalgiatension headachesmyofascial pain syndrome, and mechanical low back or neck pain.Involvement of local factors