New markers for drug discovery & newly approved drugs for Pain

1. Pain management - Novel trends
Haripriya Uppala
Department of Pharmacology
SVMC, Tirupati.

2. References...
• Goodman & Gilman’s The Pharmacological basis of
Therapeutics, 12th Ed.
• Nature Reviews Drug discovery 2014.
• Journal of Arthritis Rheumatologia 2015.
• The ASPET Pharmacological Reviews 2013.
• Frontiers in Pharmacology Dec 2013.
• British Journal of Pharmacology 2012.
• Annals of Palliative Medicine Oct 2014.
• WHO website...

3. As we go...
• Pain – Classification
• Pain – Theories
• Traditional concepts in pain management
• Novel Drug Targets
• Novel Concepts in Pain management.
• Under Research

4. Pain...
• Pain [Latin: Peona] = Punishment/ Penalty
• Pain is an unpleasant sensory and emotional
experience associated with actual or potential tissue
damage, or described in terms of such damage.
• Most common reason for visiting a doctor.
• Main cause of suffering in health care.

5. • Pain is part of the body's defense system,
producing a reflexive retraction from the painful
stimulus, and tendencies to protect the affected
body part while it heals, and avoid that harmful
situation in the future.

6. Classification of Pain
• Protective (Nociceptive)
• Reparative (Inflammatory)
• Pathological (Neuropathic)

7. Classification of Pain
• Somatogenic = is pain with cause localised in the
body
• Psychogenic = is pain for which there is no known
physical cause but processing of sensitive
information in CNS is disturbed

12. Classification of Pain
• Acute  < 6months
• Chronic > 6 months

13. Classification of Pain
Acute
• Generally protective
• Relieved when healing
complete
• Short duration
• Predictable pathology
• Predictable prognosis
• Tx with analgesics
Chronic
• Generally no useful fnctn.
• Persists after healing
complete
• Long duration
• Unpredictable Pathology
• Unpredictable prognosis
• Tx multidisciplinary

14. Chronic Pain Conditions
Nocioceptive Pain:
• Osteoarthritis
Mixed Pain:
•Malignant/cancer pain
•Chronic headache
•Fibromyalgia
•Failed back surgery syndrome
•Spastic muscle pain
Neuropathic Pain:
•CRPS 1 and CRPS 2
•Chronic abdominal pain
•Chronic pelvic pain
•Diabetic neuropathy
•HIV neuropathy
•Phantom limb pain
•Arachnoiditis
•Post herpetic neuralgia
•Post thoracotomy pain
•Trigeminal neuralgia
•Degenerative disc disease

15. Factors Contributing to Chronic Pain
“Chronic Pain Load”
• Intensity of injury
• Duration of injury
• Repetitiveness of injury
• Chronicity of underlying disease
• Genetic predisposition
▫ TrkA NGF receptor mutations
▫ BH4 enzyme production
• Other factors:
- Psychological
- Socioeconomic
- Cultural

16. Theories...
• Gate control theory – widely accepted logical
theory till date.

17. 3
2
1

18. Neuromatrix theory for Pain
• The neuromatrix theory of pain states that the
perception of painful stimuli does not result from the
brain's passive registration of tissue trauma, but from
its active generation of subjective experiences through
a network of neurons known as the neuromatrix.
• The theory was proposed by Ronald Melzack in 1996.
• Recent research has identified the anterior cingulate
cortex as a critical part of the neuromatrix.

20. Pain Detection
Nociceptors & Infl
factors
Mech/ Thermal/
Chemical Stimuln
Pain Transmission
Peripheral nerve fibers
Spinal tracts
Midbrain
Thalamus
Pain modulation
Seratonergic &
noradrenergic
descending pathways
Neurotransmitters
( 5HT, NorEp, Sub-P)
Pain expression
??????
Cultural expectations
Personality
Experiences
Emotional states
Pain Conduction Pathways

21. Sites of Pain therapy

22. Site of action of analgesics

23. 1986 WHO Analgesic ladder

24. Pain
Step 1  Nonopioid
 Adjuvant
Pain persisting or increasing
Step 2 Opioid for mild to moderate pain
 Short acting opoid 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 3- Step Analgesic Ladder
Proposed 4th Step
The WHO
Ladder
Deer, et al., 1999
8 -10
4 - 7
1 - 3
Pain
Severity

25. Rungs to Platforms

26. OPIOIDS
• MORPHINE = Potent analgesic – for acute/chronic
cancer pain, post operative pain
• FENTANYL = Extremely potent analgesic –
1. Post operative analgesia
2. Labour analgesia
3. Neuroleptanalgesia
4. Cancer pain

27. • METHADONE = neuropathic pain
• PENTAZOCINE = spinal level analgesia
• TRAMADOL = Acute severe pain – no
psychological dependance
• TAPENDELOL = centrally acting – for acute severe
pain in adults >18yrs

28. Intracellular mechanism•Inhibition of adenylyl cyclase
activity
•Reduced opening of voltage-
gated Ca2+ channels
Stimulation of K+
current through
rectifying K+
channels (GIRKs)
B-arrestin

29. •Supraspinal
•Spinal
•Perpheral

31. Embeda
• Morphine sulfate and naltrexone hydrochloride
• ER capsules is a long-acting Schedule II opioid analgesic
• Moderate to severe pain
• When a continuous, around-the-clock opioid analgesic is needed
for an extended period of time FDA approval
2014!!

32. Contd..
Liposome-encapsulated extended release morphine
• –Single epidural injection lasting 48h
• –SE –vomiting, pruritus, O2 desaturation
Intranasal opioid aerosols
• –Fentanyl, Morphine
• –Breath activated nebuliser
• –Rapid onset, deep-lung dosing
DepoFoam™Particle(di
ameter: 15 microns)
The non-concentric vesicles are surrounded by a
lipid membrane, and each contains an internal
aqueous chamber with morphine sulfate solution

33. OXYCODONE
• Semi-synthetic opioid synthesized from poppy-derived thebaine
• κ-opioid agonist
• After a dose of conventional oral oxycodone, peak plasma levels
of the drug are attained in about one hour
• Oxycodone is metabolized to α and β oxycodone The oral
bioavailability is 60% to 87%
• t ½ -4.5 hours
• mainly excreted in the urine and sweat
• Dependence, addiction and withdrawal.
• Oral/iv 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg
• Controlled release

34. Fentanyl Iontophoresis transdermal system
• Electrotransport delivery platform technology (E-
TRANS/IONSYS)
• Hydrogel reservoir into the skin
• Low-intensity direct current
• Bolus dose 40 ug
• Dose interval 10 min
• Upto 24 hours or a maximum of 80 doses
• Audible beep & LED light indicator

35. Tapendalol
•
•
• four stereoisomers .RR, SS,RS and SR forms and
RR form – approved as analgesic.
Oral absorption rapid
• Crosses the blood–brain barrier; a rapid onset of action
• t ½ = 4hrs
Is present in the serum in the form of conjugated metabolites
Excretion was exclusively renal
1. FDA approved
tapentadol in
2008
2. moderate-to-
severe acute
pain in patients
older than 18
years

36. Opioids--The Evolving Controversy
Past: Decreased Scrutiny
• 1990: Pain becomes “fifth vital sign”
• 1990: Intractable Pain Act
▫ “no physician or surgeon shall be subject to
disciplinary action …for prescribing controlled
substances for intractable pain”
• Medical Board CA defines under treatment of
pain as “inappropriate prescribing”
• 2000-2005 a 35-50% increase in opioid
prescribing

37. Opioids--The Evolving Controversy
Present: Increased Scrutiny
• Most common class of medication prescribed
▫ 800% increase in 10 years
• Fatal opioid poisonings have tripled 1999-2006
• Food & Drug Administration Act (2007)
▫ Creation of REMS for new and existing drugs
• McLellan and Turner, Annals On Internal,
Editorial, Jan 2010
- “prescribing opioids at high doses is both dangerous amd
questionable”
- White House Office of National Drug Control Policy

38. Opioids--The Evolving Controversy
Future:
• Goals
▫ Avoid undertreatment AND avoid abuse
• Know appropriate prescribing stratagies
▫ immediate release vs. sustained release formulations
▫ neuropathic vs nocioceptive pain
▫ malignant vs. chronic non-cancer pain
▫ Urine toxicology screen
▫ Opioid contract/Prescription monitoring

39. Strategic Opioid Prescribing
Prescription Monitoring
• CURES (CA)
• Pharmacists, physicians,
and law enforcement
officials
• Real time, S II – IV
• https://pmp.doj.ca.gov/p
mpreg
Opioid Contract
• Call it “Opioid
Consent”
• Discuss risks and
benefits of opioids
• Educational
• Establish rules of
prescribing

40. NSAIDs & COX Inhibitors – Inflammatory
pain

42. Intravenous Paracetamol
Adv: Propacetamol
reduces PCA morphine
Disadvantage: it must be
reconstituted before use
i.v. formulation.
May have a safety
advantage over the oral -
predictable plasma
concentrations in the
immediate postoperative
period!!!

43. Nitroxyparacetamol
• New potent NO-releasing version of paracetamol
• Suppression of synthesis of several proinflammatory cytokines
Analgesic and anti-inflammatory properties.
• Nitroxyparacetamol may be less hepatotoxic
More potent antinociceptive, anti-inflammatory effect than
paracetamol
• 20 times more potent than paracetamol
Gaitan G et al. Life Sciences 2005;77:85-
95.

44. FDA status of NSAIDs
Selective COX-2 inhibitors (Coxibs)
• Celecoxib (FDA alert)
• 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

45. • Diclofenac – most commonly prescribed NSAID for
acute pain in many countries is withdrawn fro US
market
• Reason: It has killed Vultures leading to their
extinction in India

46. Diclofenac – Colestyramine = Iontophoresis
• Faster speed of onset of action
• Better efficacy
• Dual quick-slow action
• Better compliance with twice-daily dosing in
chronic conditions like arthritis.
• Better tolerability for the resinate in comparison
to traditional diclofenac preparations, especially
GI disturbances.
• Diclofenac-colestyramine was also found not to
affect renal function when used for short-term
therapy.

47. FDA-Approved Treatments for Neuropathic Pain
• Carbamazepine
▫ trigeminal neuralgia
• Duloxetine
▫ peripheral diabetic neuropathy
• Gabapentin
▫ postherpetic neuralgia
• Lidocaine Patch 5%
▫ postherpetic neuralgia
• Pregabalin
▫ peripheral diabetic neuropathy
▫ postherpetic neuralgia

48. Neuronal potassium channel openers
FLUPIRTINE
• Neuralgias
• Chr MSK pain
• Migraine
• Fibromyalgia

49. Capsacin
• Capsaicinoids first recorded use, in the form of chilies, for
the treatment of pain dates back to 4000 BC

50. • HC capsaicin: 8% patch and 10–20% liquid Formulations
▫ Attempts to dose dependently hasten the
desensitization/defunctionalization state and therefore pain relief
▫ Safe and generally well tolerated.
▫ Dermal irritation, erythema and pain at the site of application.

51. Cannabinoids
• CB1-selective agonists reduce pain
• Periaqueductal gray matter
• THC and morphine augment each other’s effects -
possibility of combined use
• Oral THC and smoked marijuana work together
onset of action faster with smoking
• New water-soluble esters of THC-acid analogs
▫ analgesic and anti-inflammatory action
▫ no psychoactivity, no gastric irritation
▫ possible replacement for NSAIDs?
Anandamide -
mimic THC

52. Newer Muscle relaxant
• EPIRISONE
• Spastic paralysis in conditions such as cerebrovascular
disease
• Spastic spinal paralysis
• Cervical spondylosis
• Postoperative sequelae (including from cerebrospinal
tumour)
• Sequelae to trauma (e.g. spinal trauma or head injury)
• Amyotrophic lateral sclerosis
• Cerebral palsy
• Cervical syndrome, periarthritis of the shoulder,
and lumbago.

53. Novel Drug targets (since 2008)
• Neurotransmitters –SNRI (duloxetine)
• Na channels –Lamotrigine
• Ca channels –Gabapentin, pregabalin
• Glureceptor antagonist –Topiramate
• COX-2 inhibitors –celecoxib, etoricoxib, parecoxib,
lumiracoxib
• Dual 5-LOX/COX Inhibitor - Licofelone

54. Contd.,
• TRPV = Transient receptor potential vanilloid
subfamily 1-4
• Cannabinoid receptors = Tetrahydrocannabinol
• NMDA receptors = Ketamine, Memantine,
Amantidine
• Nitric oxide releasers = Nitroxyparacetamol

55. Recent Drug targets
• Adenosine receptors
• TRPC
• TRPM
• Imidazoline I2
• Chemokines
• Proteases
• CGRP
• HCN = Hyperpolarisation activated Cyclic
Nucleotide gated K+ channel

56. • Mas-Related G Protein-Coupled Receptors
• WNT pathway signalling
• GABA A receptors
• Neuronal 5HT3 receptors
• Neuronal nicotinic receptors

59. Novel concepts in Pain management
• Multimodal Analgesia
• Agents with different mechanisms of analgesia
that may have synergistic effects in preventing or
treating acute pain when used in combination.
• Captures the effectiveness of individual agents in
optimal dosages that maximize efficacy and
attempts to minimize side effects from one
analgesic.

60. • Targeted Drug delivery
• Limited drug penetration is an obstacle that is
often encountered in treatment of central nervous
system (CNS) diseases including pain and cerebral
hypoxia.
• Targets – organic anion–transporting polypeptides
(OATPs)
• Substrates - opioid analgesic peptides, 3-hydroxy-
3-methylglutaryl coenzyme A reductase inhibitors.
• Further research needed

61. New drugs...(2010-16)
• Onzetra Xsail - Sumatriptan nasal powder - for Migraine 2016
• Meloxicam - for OA 2015
• IV Diclofenac Na Injection for mild to severe pain 2014
• Oxycodone + Naloxone ER for management of chronic pain 2014.
• Low dose Indomethacin submicron particles for acute pain 2014
• Hydrocodone bitartrate ER for severe pain 2013
• Pregabalin for neuropathic pain a/w SC injury 2012
• Fentanyl Sublingual spray ( Subsys) for Breakthrough cancer pain
2012

62. • Fentanyl Sublingual tablets(Abstral) for Breakthrough cancer
pain in opioid tolerant pts 2011
• Fentanyl citrate nasal spray (Lazanda) for Breakthrough cancer
pain 2011
• Oxycodone HCl for acute/ chronic mod-sev pain 2011
• Buprenorphine transdermal system for chronic mod-sev pain
2010
• Hydromorphone HCl ER mod-sev pain 2010
Ketorolac tromethamine intranasal mod-sev pain 2010

63. Drugs under trials
• ASP3662
• ABT-981
• ABT-102
• Tapentadol (for long term treatment)
• Oxymorphone