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. Definition An 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

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)

13. Increased cortisol

14. Increased antidiuretic hormone

15. Increased growth hormone

16. Increased renin, angiotensin II, aldosterone

17. Increased glucagons

19. Acute versus Chronic Pain

20. Pain Measurement

21. Sites for pain treatment

22. Treatment Four main treatment groups: Acute pain, Chronic pain Recurrent pain, and Chronic pain of malignancy.

23. Treatment Chronic pain Patients should be using acetaminophen if not contraindicated and An 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 pain European Journal of Neurology 2010, 17: 1113–1123 Institute for Clinical Systems Improvement, Assessment and Management of Chronic Pain, Fourth Edition/November 2009

26. Treatment of chronic Cancer pain INCIDENCE OF PAIN Over 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 pain Treatment 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 pain Treatment 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 injection Annals of Oncology 20 (Supplement 4): iv170–iv173, 2009

31. Treatment of chronic Cancer pain Treatment 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 done cautiously 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 drug NSAIDs

34. Application of NSAIDs Rheumatoid arthritis Osteoarthritis Inflammatory arthropathies (e.g. ankylosingspondylitis, psoriatic arthritis, Reiter's syndrome) Acute gout Dysmenorrhoea (menstrual pain) Metastatic bone pain Headache and migraine Postoperative pain Mild-to-moderate pain due to inflammation and tissue injury Pyrexia (fever) Ileus Renal colic They are also given to neonate infants whose ductusarteriosus is not closed within 24 hours of birth Prevention of colorectal cancer. Treatment of cancer and cardiovascular disease.

35. Classification Salicylates Aspirin (acetylsalicylic acid) Diflunisal Salsalate Fenamic acid derivatives Mefenamic acid Meclofenamic acid Flufenamic acid Tolfenamic acid Propionic acid derivatives Ibuprofen Naproxen Fenoprofen Ketoprofen Flurbiprofen Oxaprozin Loxoprofen Acetic acid derivatives Indomethacin Sulindac Etodolac Ketorolac Diclofenac (Safety alert by FDA) Nabumetone Enolic acid derivatives Piroxicam Meloxicam Tenoxicam Droxicam Lornoxicam Isoxicam

36. Classification Selective COX-2 inhibitors (Coxibs) Celecoxib (FDA alert)1 Rofecoxib (withdrawn from market) Valdecoxib (withdrawn from market) Parecoxib FDA withdrawn, licenced in the EU Etoricoxib FDA withdrawn, licenced in the EU Firocoxib used in dogs and horses Sulphonanilides Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity) Others Licofelone acts by inhibiting LOX & COX and hence known as 5-LOX/COX inhibitor http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvid

37. Differences between different NSAIDs There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses1 Differences present are with regards to Dosing regimens (related to the compound's elimination half-life), Route of administration, and Tolerability profile Regarding adverse effects selective 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 toxicity1 High risk History 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 anticoagulants Low risk No risk factors H. 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 NSAIDs Question 1 Are there differences in effectiveness between NSAIDs? Question 2 & 3 Are there clinically important differences in short-term (< 6 months) or long-term (≥ 6 months) harms between NSAIDs? Question 4 Are 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 & Tapentadol Dual Analgesic Mechanisms

42. Tramadol Opioid Activity Tramadol produces antinociception via predominantly, a mu-opioid receptor mechanism. No respiratory depression, sedation, or constipation, as observed with other opiates. No analgesic tolerance No psychological dependence or euphoric effects in long-term clinical trials Monoaminergic Activity Noradrenergic and serotonergic neurons originate in the brainstem and terminate in the dorsal horn of the spinal cord Monoaminergic pathway modulates the spinal processing of nociception through the section of norepinephrine and serotonin Tramadol’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. Tramadol CYP2D6 Pathway Tramadol 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 reuptake Tramadol 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. Tramadol Efficacy Effective and well-tolerated analgesic in all 3 forms of administration.(PO,IV,PR) Onset of analgesia is within 30 minutes Duration of action from 3 to 7 hours Drowsiness is the most frequent side effect No adverse effects were observed in the parturient after labor or in the newborn when given for Labour pain relief

45. Tramadol Routes of adminsitration PO IV PR Intra-thecal Epidural

46. Tramadol Adverse Events Dependence Withdrawal symptoms after abrupt discontinuation or reduction of dose. hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and unusual sensory experiences can occur in rare cases Serotonin Syndrome Minor possibility of this exists with both tramadol and tapentadol Avoid concurrent administration of SSRI’s or selective-norepinephrine reuptake inhibitors, triptans, or tricyclic antidepressants

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

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

49. Tapentadol Pharmacokinetics Oral absorption of tapentadol is rapid Is present in the serum in the form of conjugated metabolites Excretion was exclusively renal (99%: 69% conjugates; 27% other metabolites; 3% in unchanged form)

50. Skeletal Muscle Relaxants Use to treat 2 different types of conditions Spasticity Muscular pain or spasms upper motor neuron syndromes peripheral musculoskeletal conditions Associated with exaggerated cutaneous reflexes, autonomic hyper-reflexia, dystonia, contractures, paresis, and fatigability Fibromyalgia tension headaches myofascial pain syndrome, and mechanical low back or neck pain. Involvement of local factors

51. Drugs classified as skeletal muscle relaxants Baclofen, Carisoprodol, Chlorzoxazone, Cyclobenzaprine, Dantrolene, Metaxalone, Methocarbamol, Orphenadrine, and Tizanidine. Drugs approved for the treatment of spasticity Baclofen :blocks pre- and post-synaptic GABAB receptors Dantrolene :centrally acting agonist of α2 receptors Tizanidine :directly inhibits muscle contraction by decreasing the release of calcium from skeletal muscle sarcoplasmic reticulum

52. Key question 1 What is the comparative efficacy of different muscle relaxants in reducing symptoms and improving functional outcomes in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms? Key question 2 What are the comparative incidence and nature of adverse effects (including addiction and abuse) of different muscle relaxants in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms? Key question 3 Are there subpopulations of patients for which one muscle relaxant is more effective or associated with fewer adverse effects? Answer in Document 2, provided

53. The Newer Muscle Relaxant Epirisone 4′-ethyl-2-methyl-3-piperidinopropiophenone hydrochloride) Inhibits gamma-efferent firing and local vasodilatation activity

54. Epirisone Potential indications Spastic paralysis in conditions such as cerebrovascular disease Spastic spinal paralysis Cervical spondylosis[1] Postoperative sequelae (including from cerebrospinal tumour)[2] Sequelae to trauma (e.g. spinal trauma or head injury)[2] Amyotrophic lateral sclerosis Cerebral palsy Spinocerebellar degeneration Spinal vascular diseases and other encephalomyelopathies Cervical syndrome, periarthritis of the shoulder, and lumbago.[3 Methods Find Exp Clin Pharmacol 21 (3): 209 http://www.europeanreview.org/article_download/502 Myonil (Eperisone) Pack insert form square pharma

55. Epirisone Actions of Epirisone Skeletal muscle relaxation Relaxation of hypertonic skeletal muscles Improves intramuscular blood flow Suppression of spinal reflex potentials Reduction of muscle spindle sensitivity via motor neurons Vasodilatation and augmentation of blood flow Analgesic action and inhibition of the pain reflex in the spinal cord

56. Epirisone Possible Mechanisms of Action

57. Certain studies available for the efficacy of Eperisone Efficacy and tolerability of eperisone in patients with spastic palsy: a cross-over, placebo-controlled dose-ranging trial. Bresolin N, Zucca C, Pecori A. Eur Rev Med Pharmacol Sci. 2009 Sep-Oct;13(5):365-70. Efficacy and tolerability of eperisone and baclofen in spastic palsy: a double-blind randomized trial. Bresolin N, Zucca C, Pecori A. Adv Ther. 2009 May;26(5):563-73. Epub 2009 May 20. Open experience with a new myorelaxant agent for low back pain. Sartini S, Guerra L. Adv Ther. 2008 Oct;25(10):1010-8. Clinical experience with eperisone in the treatment of acute low back pain. Beltrame A, Grangiè S, Guerra L. Minerva Med. 2008 Aug;99(4):347-52. Eperisone compared to physiotherapy on muscular tone of stroke patients: a prospective randomized open study. Tariq M, Akhtar N, Ali M, Rao S, Badshah M, Irshad M. J Pak Med Assoc. 2005 May;55(5):202-4.

58. Sodium Channel Blockers in Neuropathic Pain sodium channels are involved in the development of certain types of neuropathic pains After nerve injury hyperexcitability develops at the site of injury and also in the dorsal root ganglion cell bodies hyperexcitability results from accumulation of sodium channels at the site of injury The fact These sodium channels seem to exist in peripheral nerves only and that they can be blocked at the resting state the most potent drugs that are currently used to manage neuropathic pain are TCA, most Anticonvulsants, Anesthetics.

59. Flupirtine Selective neuronal potassium channel openers

60. Introduction Ion channels play a vital role in pain signal initiation and conduction Less attention has been paid to the role of K+ channels in pain K+ channels play an essential role in setting the resting membrane potential and in controlling the excitability of neurons K+ channels represent potentially attractive peripheral targets for the treatment of pain

61. Flupirtine Probable Mechanism of Action Site of Action – CNS (Both Spinal and Supra spinal involvement of descending adrenergic pathways Initial studies (indirect) action at N-Methyl-D-aspartate (NMDA) receptors Antagonist action Subsequent studies activation of a G-protein regulated inwardly rectifying K(+) (GIRK) ion channel Present J Clin PharmTher. 2010 Nov 28. doi: 10.1111/j.1365-2710.2010.01233.x. [Epub ahead of print]

62. Flupirtine Actions and Indications Chronic musculoskeletal pain Migraine and Neuralgias Fibromyalgias Flupirtin’s analgesic and muscle-relaxant properties were comparable to tramadol. CNS Drugs. 2010 Oct 1;24(10):867-81

63. Flupirtine Side effect profile The most common adverse effects Drowsiness Dizziness Heartburn Dry mouth Fatigue and Nausea