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Dr. Ashutosh Tiwari
PG Resident (III yr.)
Department of Pharmacology, SAIMS
09/04/16
 Mechanisms of pain transmission & modulation
 Mechanism of anti-nociceptive activity of various
analgesics
 Recent adv...
 Pain is an unpleasant sensation that originates from ongoing
or impending tissue damage.
 For decades, we have been pri...
 Pain perception results from a series of signaling events
occurring within the PNS and CNS.
 Transduction – the process...
Painful stimuli
Activation of specialized nerve
endings (peripheral nociceptors)
opening of ion channels and flux
of ions ...
Dorsal horn of
spinal cord
release of
excitatory neurotransmitters (e.g., glutamate),
neuropeptides (e.g., substance P)
ne...
 Pro-inflammatory factors
 bradykinin, prostaglandin E2, nerve growth factor
and tumor necrosis factor alpha (TNF-α) 
...
 Peripheral sensitization
 Peripheral nociceptive afferent activation
following an inflammatory response 
 augmented b...
 Central sensitization
 continued impulse activity in the periphery 
 neurons in the CNS can undergo changes that
incr...
 Persistent desensitization
 Paradoxically, a noxious stimulus that initially leads to
sensitization, such as that cause...
 Descending pain suppression pathway
 To counteract pain facilitatory input, activation of
descending pain suppression p...
 Monoaminergic neurotransmitters such as
 norepinephrine, serotonin and dopamine modulate
pain signaling within the dors...
 Descending serotonergic pathways
 inhibit nociceptive signaling via 5-HT1 receptor
activation
 can promote nociceptive...
 Descending dopaminergic pathways
 can either inhibit or facilitate nociceptive
signaling
 inhibit nociceptive signalin...
 Descending noradrenergic pathways
 In contrast to serotonergic and dopaminergic receptor-
mediated activity, each of wh...
 alpha-2-adrenoceptors mediate inhibitory
descending brain stem control over dorsal horn
nociceptive traffic and
 the se...
 Local anesthetics such as lidocaine exert their antinociceptive
effect by
 blocking sodium channels within neuronal mem...
 most commonly used for the management of acute
and chronic musculoskeletal and post-surgical pain
 primary mechanism of...
 similar analgesic and antipyretic properties to
NSAIDs, but lacks anti-inflammatory properties
 inhibits cyclooxygenase...
 bind to the α2-𝞭 subunit of voltage- dependent calcium
channels within neuronal membranes 
 inhibit the release of exc...
 mainstay of therapy for the management of moderate to severe
nociceptive pain
 generally considered second-line therapy...
 include
 tricyclic antidepressants (TCAs; e.g.,
amitriptyline, clomipramine, desipramine,
imipramine)
 serotonin and n...
 Monoamine re-uptake inhibitors promote analgesia by
 increasing the synaptic concentration of norepinephrine (NE)
and/o...
 patients can control their pain by self-administration of
intravenous opioids using patient-controlled analgesia (PCA)
d...
 Lipophilic opioids have been used in the form of
transdermal patches
 Fentanyl and buprenorphine are used
transdermally...
 Accumulation of fentanyl can occur
with the use of patches
 administration of low doses of fentanyl
hydrochloride by io...
 This technique has been investigated for fentanyl,
alfentanil, sufentanil, pethidine (meperidine),
diamorphine and butor...
 only been developed for oxycodone hydrochloride
 demonstrated fast pain relief in an acute animal
model
 therefore, fu...
 More recently available
acetaminophen preparation for
IV infusion has increased its
usefulness, particularly in
perioper...
 There are no recent new substances in this class of
analgesics; however, new preparations of older
compounds are in deve...
There is only one new molecule, tapentadol,
in this group approved in Nov. 2008
dual mode of action as an agonist of the...
 Fentanyl was initially developed for parenteral administration
 oral route being of limited use due to high first pass
...
 Now a variety of immediate
release formulations have
become available recently
 Oral transmucosal
fentanyl citrate (OTF...
delivered to the periphery
of the lungs
leads to rapid absorption
into the systemic
circulation.
Controlled uptake of
f...
 Opioids are only indicated for the treatment of breakthrough
pain in opioid-tolerant cancer pain patients
 but high rat...
Examples
 Mechanical / physical barrier:
 slow-release oxycodone formulation having combination of a
 mechanical barrie...
 Tramadol, although not a new opioid but recently rediscovered,
that has been shown to be effective
 in the treatment of...
 Methadone has been used in maintenance programmes for
opioid addiction
 However, methadone is being increasingly recogn...
 Opioid-related constipation is one of the most frequent adverse
effects of chronic pain treatment.
 Enteral administrat...
 Alpha-2-delta modulators (gabapentin and
pregabalin)
 Serotonin-norepinephrine reuptake inhibitors
(SNRIs)
 Ketamine
...
 Gabapentin and pregabalin are anticonvulsant
drugs that act by binding to the alpha-2-delta
subunit of voltage gated cal...
 Effective in the treatment of neuropathic pain from a variety
of causes
 like post-herpetic neuralgia, diabetic polyneu...
 Lamotrigine is another new antiepileptic drug
 blocks voltage-dependent sodium channels
 inhibits glutamate release
 ...
 Antidepressants have long been used in the
management of chronic pain
 tricyclic antidepressants (TCAs), in particular
...
 For SNRIs there are now sufficient data for their efficacy
in neuropathic pain states
 for treatment of diabetic polyne...
 originally introduced into clinical practice as a dissociative
anaesthetic in 1963
 mechanism of action:
 antagonism a...
 ketamine has shown some efficacy in the treatment
of acute neuropathic pain, e.g., after spinal cord
injury or after maj...
 Calcitonin is a polypeptide hormone produced
naturally by the para-follicular cells of the thyroid
gland
 It was common...
 Cannabinoids comprise a large group of chemical
compounds that act upon the cannabinoid receptor.
 Ex. cannabidiol (CBD...
 CB1 receptors
 found mainly within the brain
 however absent from the medulla oblongata, possibly explaining
the lack ...
 Several studies have found that preoperative
dexamethasone improves acute postoperative pain
(however, not in all studie...
 Lidocaine plaster
 Topical capsaicin
 Lidocaine is one of the most commonly used local anesthetic
agents in anesthesia and pain management.
 Peripheral mecha...
 Capsaicin (8-methyl-N-vanillyl-6-nonenamide), is the pungent
ingredient of chilli peppers,
 binds to the transient rece...
 Pain is a multifactorial phenomenon and knowledge of the
complexity of pain pathways is growing, as demonstrated by
curr...
 combined opioid and non-opioid agents have
demonstrated that this approach
 reduced consumption of opioid analgesics
 ...
 Major emerging drug targets for pain treatment:
 Transient receptor potential ankyrin (TRPA) 1
channel
 Cannabinoid CB...
 Transient receptor potential ankyrin 1 (TRPA1) is a member of
the TRP channel superfamily that is expressed on primary
a...
 The primary active ingredient of cannabis, Δ9-
tetrahydrocannabinol, binds to and activates two G
protein-coupled recept...
 CB2 receptors are also located in the brain
microglia, particularly under some pathological
conditions (e.g., neuroinfla...
 Sativex, a buccal formulation
(sublingual spray) of cannabis
extract with fixed 1:1 ratios of
Δ9-tetrahydrocannabinol an...
 the inhibitory neurons in the spinal cord dorsal horn
control the transmission of “pain” signals from the
periphery to h...
 functionality of the different α subunits:
 α1 subunits are primarily involved in the sedative
effects
 α2/α3 subunits...
 I2 receptor agonists are effective for alleviating
acute visceral, inflammatory and neuropathic pain.
 In addition, I2 ...
 Many treatment modalities are being used to reduce and
alleviate pain.
 However, many clinical questions are still unan...
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
Recent advances in Pain treatment
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Recent advances in Pain treatment

Recent advances in the pharmacological treatment of pain

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Recent advances in Pain treatment

  1. 1. Dr. Ashutosh Tiwari PG Resident (III yr.) Department of Pharmacology, SAIMS 09/04/16
  2. 2.  Mechanisms of pain transmission & modulation  Mechanism of anti-nociceptive activity of various analgesics  Recent advances in the field of pharmacological pain therapy  New Modalities of drug administration  Recent advances in the existing pain treatment  Novel targets for pain treatment
  3. 3.  Pain is an unpleasant sensation that originates from ongoing or impending tissue damage.  For decades, we have been primarily relying upon  opioids and  nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management.  However, adverse effects related to opioid and NSAID use are severe and often lead to forced drug discontinuation and inadequate pain relief.  Despite decades of research, currently available pharmacotherapies for pain still fall short of clinical needs.  With increased understanding of the neurobiology and pathophysiology of pain, new drug targets have been emerging, which may lead to novel therapeutic strategies.
  4. 4.  Pain perception results from a series of signaling events occurring within the PNS and CNS.  Transduction – the process by which noxious stimuli are electrical activity converted into within the PNS
  5. 5. Painful stimuli Activation of specialized nerve endings (peripheral nociceptors) opening of ion channels and flux of ions across cell membranes depolarization and generation of action potentials conducted via peripheral afferents to the dorsal horn of the spinal cord
  6. 6. Dorsal horn of spinal cord release of excitatory neurotransmitters (e.g., glutamate), neuropeptides (e.g., substance P) neuromodulators (e.g., BDNF) from axon terminals into the synapse bind to and activate receptors on the post- synaptic nerve terminal: NMDA, AMPA, G-protein-coupled receptors and tyrosine kinase receptors impulses generated in the dorsal horn travel through ascending pathways (e.g., the spinothalamic tract) to the brain In the brain signals are processed and pain is perceived
  7. 7.  Pro-inflammatory factors  bradykinin, prostaglandin E2, nerve growth factor and tumor necrosis factor alpha (TNF-α)   bind to specific receptors on neuronal terminals   sensitize the nerve terminal (i.e., lower the threshold for activation) &  can depolarize primary afferents directly by activating sodium ion channels
  8. 8.  Peripheral sensitization  Peripheral nociceptive afferent activation following an inflammatory response   augmented by changes in the expression of certain ion channels and synaptic modulators within sensory nerves   increased levels of the heat-sensitive transient receptor potential vanilloid type 1 (TRPV1) channel in peripheral nociceptor terminals, and elevations of the synaptic modulator BDNF   amplify input to the spinal cord   increased state of excitability and increased sensitivity to nociceptive input
  9. 9.  Central sensitization  continued impulse activity in the periphery   neurons in the CNS can undergo changes that increase their excitability   activation of pain pathways by stimuli that are normally subthreshold (allodynia) or cause  exaggerated responses to normally suprathreshold stimuli (hyperalgesia)  Activation of the NMDA receptor plays a key role in increasing CNS excitability (central sensitization)
  10. 10.  Persistent desensitization  Paradoxically, a noxious stimulus that initially leads to sensitization, such as that caused by the TRPV1 agonist capsaicin, can subsequently cause persistent desensitization  Capsaicin administration triggers   loss of peripheral and/or central nociceptor-specific macromolecules and receptors   neurodegenerative changes in primary sensory neurons   reduced effectiveness of synaptic transmission at the dorsal horn  Capsaicin treatment provides some level of pain relief for chronic neuropathic pain,  although an initial burning sensation persisting for days due to peripheral sensitization is a distinct disadvantage
  11. 11.  Descending pain suppression pathway  To counteract pain facilitatory input, activation of descending pain suppression pathways   reduce the likelihood that a stimulus is perceived as painful or reduce the perceived intensity of pain.  Endogenous opioids are involved in the descending inhibitory pathways   Structures in the midbrain (periaqueductal gray) send projections to the spinal dorsal horn   modulate nociceptive neuronal activity through release of endogenous opioids  inhibit pain signal transmission
  12. 12.  Monoaminergic neurotransmitters such as  norepinephrine, serotonin and dopamine modulate pain signaling within the dorsal horn   these neurotransmitters can exert either antinociceptive or pronociceptive effects, depending upon the subtype and location of the receptors involved
  13. 13.  Descending serotonergic pathways  inhibit nociceptive signaling via 5-HT1 receptor activation  can promote nociceptive transmission by activating 5-HT2/3 neurons  activation of 5-HT1A receptors   inhibits the excitability of spinothalamic projecting neurons and excitatory (i.e., pain facilitatory) interneurons  5-HT1B/D receptor activation   inhibition of neuro- transmitter release from primary nociceptive afferents (antinociceptive action)
  14. 14.  Descending dopaminergic pathways  can either inhibit or facilitate nociceptive signaling  inhibit nociceptive signaling by  activating D2 and D3 receptors on primary nociceptive afferents and neurons in the dorsal horn  inhibit pre-synaptic neurotransmitter release  dopamine can be pronociceptive if  it activates D1 spinothalamic projecting (i.e., ascending) neurons
  15. 15.  Descending noradrenergic pathways  In contrast to serotonergic and dopaminergic receptor- mediated activity, each of which have pro- and antinociceptive effects,  descending noradrenergic pathway activation is only known to have antinociceptive effects  Descending noradrenergic pathways (from pontine region) projecting to the spinal dorsal horn   inhibit pain signaling by  activating α2A receptors on terminals of primary nociceptors, or  activating post-synaptic α1 receptors, causing release of inhibitory neurotransmitters (GABA or glycine) from inhibitory interneurons
  16. 16.  alpha-2-adrenoceptors mediate inhibitory descending brain stem control over dorsal horn nociceptive traffic and  the serotonin 5HT3 receptor facilitates dorsal horn nociceptive processing  This may be the reason why antidepressants that selectively reduce serotonin reuptake are less effective adjuvant analgesics than the ones which also inhibit norepinephrine reuptake  therefore norepinephrine reuptake inhibition is essential for the anti-nociceptive effect
  17. 17.  Local anesthetics such as lidocaine exert their antinociceptive effect by  blocking sodium channels within neuronal membranes   inhibit afferent neuronal excitability and the propagation of nociceptive input via action potentials  effective in the management of acute, post-operative pain  The lidocaine (5%) patch is a topical anesthetic recommended for the treatment of  neuropathic pain  pain associated with post-herpetic neuralgia (PHN)
  18. 18.  most commonly used for the management of acute and chronic musculoskeletal and post-surgical pain  primary mechanism of NSAID-induced analgesia  inhibition of the enzyme cyclooxygenase   reduces the production of inflammatory mediators, including the prostaglandins  may also inhibit the expression of or directly block acid-sensitive ion channels within membranes of nociceptive neurons  Used as monotherapy for mild to moderate pain, but they are primarily used as adjunct therapy in cases of severe pain
  19. 19.  similar analgesic and antipyretic properties to NSAIDs, but lacks anti-inflammatory properties  inhibits cyclooxygenase-mediated activation of prostaglandins primarily in the CNS  In addition, acts on the serotonergic inhibitory descending pathway and the endogenous opioid pathway  recommended for use in multidrug therapies for severe pain
  20. 20.  bind to the α2-𝞭 subunit of voltage- dependent calcium channels within neuronal membranes   inhibit the release of excitatory neurotransmitter by pre- synaptic neurons   In addition, may activate descending inhibitory pathways, resulting in an increase in spinal norepinephrine concentration
  21. 21.  mainstay of therapy for the management of moderate to severe nociceptive pain  generally considered second-line therapy for neuropathic pain conditions, such as diabetic peripheral neuropathy and post-herpetic neuralgia  promote analgesia through the activation of µ-opioid receptors by:  (A) decreasing pre-synaptic release of excitatory neurotransmitters,  (B) decreasing post-synaptic neuronal excitability, and  (C) promoting descending inhibition
  22. 22.  include  tricyclic antidepressants (TCAs; e.g., amitriptyline, clomipramine, desipramine, imipramine)  serotonin and norepinephrine re-uptake inhibitors (SNRIs; e.g., duloxetine and venlafaxine).  considered first-line therapy for neuropathic pain; efficacy as single agent therapy for nociceptive pain is less well established  Evidence from clinical studies indicates that agents that inhibit norepinephrine reuptake, either selectively or in addition to inhibiting serotonin re- uptake, provide more effective analgesia than those agents that selectively inhibit serotonin reuptake.
  23. 23.  Monoamine re-uptake inhibitors promote analgesia by  increasing the synaptic concentration of norepinephrine (NE) and/or serotonin (5-HT) within the dorsal horn   (A) inhibit the release of excitatory neurotransmitter by pre-synaptic neurons  (B) reducing the excitation of post-synaptic neurons; and  (C) promoting the release of other inhibitory neurotransmitters by interneurons
  24. 24.  patients can control their pain by self-administration of intravenous opioids using patient-controlled analgesia (PCA) devices  provide better pain control and greater patient satisfaction compared with conventional parenteral analgesic regimens
  25. 25.  Lipophilic opioids have been used in the form of transdermal patches  Fentanyl and buprenorphine are used transdermally  Initial use was proposed for chronic pain and more specifically for cancer pain  Currently, it is widely used in different pain conditions, but NOT in acute postoperative pain conditions  because the therapeutic concentrations are obtained between 12 and 32 hours after the patch is applied for drugs such as fentanyl.
  26. 26.  Accumulation of fentanyl can occur with the use of patches  administration of low doses of fentanyl hydrochloride by iontophoresis was developed  This technique uses a low intensity electrical current that allows fentanyl to diffuse from a reservoir to the skin to rapidly obtain an effective site concentration  This is a patient-controlled transdermal system that is easily applied to the upper outer arm or chest and provides postoperative pain control equivalent to intravenous morphine PCA.  There is no subcutaneous accumulation of fentanyl with this approach  therefore no risk of residual analgesia following its withdrawal
  27. 27.  This technique has been investigated for fentanyl, alfentanil, sufentanil, pethidine (meperidine), diamorphine and butorphanol tartrate.  It can be as effective as intravenous administration.  This new method of opioid delivery provides good bioavailability, since  it avoids hepatic first-pass metabolism because it is absorbed directly by the mucous nasal membrane.  Other advantages of this technique are  its effectiveness,  its noninvasive method of administration and ease of use
  28. 28.  only been developed for oxycodone hydrochloride  demonstrated fast pain relief in an acute animal model  therefore, further investigations are needed to assess its effectiveness in humans.
  29. 29.  More recently available acetaminophen preparation for IV infusion has increased its usefulness, particularly in perioperative setting  reduces postoperative nausea and vomiting, in particular if given prophylactically at induction of anesthesia.  reduces the requirement of opioids
  30. 30.  There are no recent new substances in this class of analgesics; however, new preparations of older compounds are in development.  Ketorolac as nasal spray, was recently approved by the FDA in 2010  Other developments are preparations, which permit use of lower doses of NSAIDs in an attempt to reduce adverse effects.  submicron particle NSAIDs (so called nano formulations) of diclofenac and indomethacin have been tested  a new formulation of injectable diclofenac sodium solubilized with hydroxypropyl-beta-cyclodextrin showed efficacy at much reduced doses
  31. 31. There is only one new molecule, tapentadol, in this group approved in Nov. 2008 dual mode of action as an agonist of the μ- opioid receptor and as a norepinephrine reuptake inhibitor multiple new formulations of opioids have been recently developed, aimed at increased speed of onset or reduced risk of abuse and diversion
  32. 32.  Fentanyl was initially developed for parenteral administration  oral route being of limited use due to high first pass metabolism  Because of its highly lipophilicity transdermal fentanyl formulations have been marketed.
  33. 33.  Now a variety of immediate release formulations have become available recently  Oral transmucosal fentanyl citrate (OTFC)  Another route of administration for TIRFs is the nasal administration  Fentanyl citrate is a new opioid formulation that incorporates fentanyl into a lozenge and allows drug delivery through the buccal mucosa
  34. 34. delivered to the periphery of the lungs leads to rapid absorption into the systemic circulation. Controlled uptake of fentanyl by the lungs and thus provide sustained drug release DepoFoam™Particle (diameter: 15 microns)
  35. 35.  Opioids are only indicated for the treatment of breakthrough pain in opioid-tolerant cancer pain patients  but high rate of off-label use in chronic and acute pain patients  A large number of deaths have been reported with these preparations if used inappropriately  The issues of abuse and diversion of opioids have resulted in an increasing interest in the development of  ‘tamper-resistant’ or ‘abuse-deterrent’ formulations  Such formulations rely on a number of technologies, which include  physical or mechanical barriers,  aversion or the addition of a noxious components and  agonist/antagonist combinations
  36. 36. Examples  Mechanical / physical barrier:  slow-release oxycodone formulation having combination of a  mechanical barrier (polymer coating makes crushing difficult) and a  physical barrier effect (viscous gel reduces ability to draw up drug for injection)  Combinations with antagonists:  naloxone (in buprenorphine or oxycodone preparations) and naltrexone (in a morphine preparation)  use of aversion by an addition of a noxious substance (niacin):  preparation of oxycodone, which was refused registration by the FDA
  37. 37.  Tramadol, although not a new opioid but recently rediscovered, that has been shown to be effective  in the treatment of neuropathic pain  produces equivalent analgesia when compared with pethidine in postoperative pain conditions  Tramadol alone or in combination with paracetamol produces a comparable relief in low back pain patients  combination of tramadol and paracetamol is as effective as the combination of hydrocodone and paracetamol in relieving acute musculoskeletal pain
  38. 38.  Methadone has been used in maintenance programmes for opioid addiction  However, methadone is being increasingly recognised as a valuable second-line opioid analgesic for  chronic noncancer pain, especially neuropathic pain  treatment of cancer pain  Methadone has undergone a renaissance because  it has high oral bioavailability  a long duration of action  lack of active metabolites  antagonist properties at NMDA receptors and  blocks the reuptake of monoamines
  39. 39.  Opioid-related constipation is one of the most frequent adverse effects of chronic pain treatment.  Enteral administration of naloxone or naltrexone  blocks opioid action at the intestinal receptor level,  but has low systemic bioavailability as a result of marked hepatic first-pass metabolism  Methylnaltrexone  peripheral opioid receptor antagonist  undergoing phase III clinical trials for the treatment of opioid- induced constipation  It does not cross the blood-brain barrier in humans and reverses the opioid effects WITHOUT interfering with pain relief.  Some opioid-induced adverse events that this kind of drug may potentially target include constipation, nausea/ vomiting, cough suppression and urinary retention.
  40. 40.  Alpha-2-delta modulators (gabapentin and pregabalin)  Serotonin-norepinephrine reuptake inhibitors (SNRIs)  Ketamine  Calcitonin  Cannabinoids
  41. 41.  Gabapentin and pregabalin are anticonvulsant drugs that act by binding to the alpha-2-delta subunit of voltage gated calcium channels within the CNS  Gabapentin and pregabalin (gabapentin analogue)  act at the α2δ subunit of the voltage-gated calcium channels   Downregulate calcium ion influx into neurons   reduce the release of a various excitatory neurotransmitters (particularly glutamate)
  42. 42.  Effective in the treatment of neuropathic pain from a variety of causes  like post-herpetic neuralgia, diabetic polyneuropathy and central neuropathic pain after spinal cord injury  Also used in some acute painful conditions  pregabalin has been used successfully is burns pain  In acute postoperative pain, gabapentin is the only anticonvulsant for which an analgesic effect on its own was identifed  Perioperative use of gabapentin and pregabalin has significant benefits in postoperative pain relief and opioid requirements  show consistently improved analgesia  opioid-sparing effect and  reduced incidence and/or severity of opioid-induced adverse effects, particularly nausea & vomiting
  43. 43.  Lamotrigine is another new antiepileptic drug  blocks voltage-dependent sodium channels  inhibits glutamate release  effective in trigeminal neuralgia, painful peripheral neuropathy and for post- stroke pain
  44. 44.  Antidepressants have long been used in the management of chronic pain  tricyclic antidepressants (TCAs), in particular amitriptyline, is commonly used in the treatment of neuropathic pain  But its adverse effects (sedation, confusion, blurred vision, postural hypotension and many others) are the main constraint to its use and reason for withdrawal of patients  Venlafaxine, is devoid of action on muscarinic- cholinergic, histaminic and α1-adrenergic receptors responsible for the common adverse effects seen with tricyclic antidepressants
  45. 45.  For SNRIs there are now sufficient data for their efficacy in neuropathic pain states  for treatment of diabetic polyneuropathy, both duloxetine and venlafaxine, show better efficacy and a better benefit-risk balance than amitriptyline  Venlafaxine is considered as effective as imipramine (tricyclic antidepressant) in the treatment of pain related to polyneuropathy  SNRIs might also be useful in conditions, typical of nociceptive pain, but with a significant component of central sensitization  duloxetine in chronic low back pain & osteoarthritis,  It is at least non-inferior to commonly used other analgesics such as NSAIDs
  46. 46.  originally introduced into clinical practice as a dissociative anaesthetic in 1963  mechanism of action:  antagonism at the NMDA receptor (a calcium channel, for which glutamate is the natural ligand)  This channel has also been linked to the phenomenon of central sensitization, a process associated with the development and maintenance of chronic pain  Ketamine reduces the level of sensitisation  Ketamine also has a number of other sites of action including  nicotinic, muscarinic, opioid, AMPA and Kainate receptors  also inhibits serotonin and dopamine reuptake  down regulates certain ion channels
  47. 47.  ketamine has shown some efficacy in the treatment of acute neuropathic pain, e.g., after spinal cord injury or after major limb trauma and after burns injury  it is also increasingly used as an adjunct to other analgesics in the postoperative and posttraumatic setting.  improved analgesia, reduced opioid consumption and less postoperative desaturation when added to opioids via PCA pumps  also very useful for the treatment of postoperative pain and cancer pain in opioid-tolerant patients  Ketamine is also increasingly used in chronic pain states
  48. 48.  Calcitonin is a polypeptide hormone produced naturally by the para-follicular cells of the thyroid gland  It was commonly used in osteoporosis and Paget’s disease.  Recent studies have suggested its efficacy in some acute and chronic pain states  Another indication is acute, but not chronic pain  caused by osteoporotic vertebral compression fractures &  phantom limb pain after amputation
  49. 49.  Cannabinoids comprise a large group of chemical compounds that act upon the cannabinoid receptor.  Ex. cannabidiol (CBD) and cannabinol (CBN)  These include:  endocannabinoids such as anandamide (produced naturally in the body by humans and animal)  phytocannabinoids (found in cannabis and some other plants), and  synthetic cannabinoids (manufactured chemically)  The primary active component is delta-9- tetrahydrocannabinol (THC), which is responsible for many of the commonly known effects.
  50. 50.  CB1 receptors  found mainly within the brain  however absent from the medulla oblongata, possibly explaining the lack of respiratory and cardiac depressive effects  responsible for the analgesic, euphoric and anticonvulsive effects  CB2 receptors  found primarily within the immune system  modulate the cytokinine system and are believed to have anti- inflammatory and immunosuppressive effects  Despite the hype and widespread use of cannabinoids for the treatment of neuropathic pain, the overall data remains confusing  but suggests limited efficacy in some neurologic disorders, mainly related to spasticity and some chronic neuropathic pain conditions, particularly those related to MS and AIDS
  51. 51.  Several studies have found that preoperative dexamethasone improves acute postoperative pain (however, not in all studies)  The mechanism by which dexamethasone improves post- operative analgesia is not well understood.  Morphine increases central nervous system glutamate levels   dexamethasone increases glutamate transporter expression   which increases glutamate clearance from synaptic clefts   Hence, dexamethasone appears to reduce morphine analgesic tolerance
  52. 52.  Lidocaine plaster  Topical capsaicin
  53. 53.  Lidocaine is one of the most commonly used local anesthetic agents in anesthesia and pain management.  Peripheral mechanisms of neuropathic pain include ectopic discharges of damaged neurons   lidocaine blocks sodium channels suppressing the formation of action potentials has a potential to be a treatment for neuropathic pain  But systemic use of lidocaine  carries the risk of systemic adverse effects and  need for parenteral administration  However, development of a plaster for topical administration of lidocaine has resulted in a new first- line treatment of localized neuropathic pain with minimal systemic adverse effects  diabetic neuropathy and post herpetic neuralgia, carpal tunnel syndrome, postsurgical and posttraumatic pain
  54. 54.  Capsaicin (8-methyl-N-vanillyl-6-nonenamide), is the pungent ingredient of chilli peppers,  binds to the transient receptor potential vanilloid 1 (TRPV1) subunits, which are located on peripheral nociceptors and also responsive to heat, acidity and endogenous metabolites of polyunsaturated fatty acids  Exposure to capsaicin results initially in a painful burning sensation due to substance P release  multiple administration of low concentration or single administration of high concentration capsaicin finally leads to reduced sensitization or even complete desensitization.  A high concentration (8%) capsaicin patch for single administration was commercially developed and is registered in a number of countries to treat neuropathic pain.
  55. 55.  Pain is a multifactorial phenomenon and knowledge of the complexity of pain pathways is growing, as demonstrated by current research.  Single-agent regimens may not provide optimal analgesia for certain types of pain because they address a limited number of therapeutic targets in the pain transmission and modulatory pathways  The concept of multimodal analgesia involves the use of different classes of analgesics and different sites of analgesic administration to provide superior dynamic pain relief with reduced analgesic- related adverse effects.  Multidrug analgesic approaches take advantage of  complementary mechanisms of different drug classes to enhance analgesia and/or  reduce adverse effects by lowering the required dose of one or more agents.  A multimodal approach is associated with an increase in patient satisfaction
  56. 56.  combined opioid and non-opioid agents have demonstrated that this approach  reduced consumption of opioid analgesics  lowered the incidence of opioid-associated side effects without sacrificing efficacy  provided superior analgesia (in some instances)  The use of nonpharmacological options as adjuvants to conventional analgesia  Ex. Acupuncture, Relaxation, transcutaneous nerve stimulation  achieves an effective and successful pain management regimen in some patients
  57. 57.  Major emerging drug targets for pain treatment:  Transient receptor potential ankyrin (TRPA) 1 channel  Cannabinoid CB2 receptors  GABAA subtype receptors  Imidazoline I2 receptors
  58. 58.  Transient receptor potential ankyrin 1 (TRPA1) is a member of the TRP channel superfamily that is expressed on primary afferent nerve fibers  activated by various exogenous irritants and diverse chemicals including many algogenic substances  There is a critical role of TRPA1 in pain induction and transduction, and TRPA1 may represent a potential drug target for pain treatment.  Theoretically, because TRPA1 agonists are pronociceptive, a drug that blocks TRPA1 (antagonist) should have pain relieving activity.  Several studies have shown that TRPA1 antagonists have strong antinociceptive activities in a broad range of animal models of inflammatory and neuropathic pain, but have little effect for acute nociception.
  59. 59.  The primary active ingredient of cannabis, Δ9- tetrahydrocannabinol, binds to and activates two G protein-coupled receptors (GPCRs), CB1 and CB2 receptors  Many of the psychoactive and analgesic effects are due to the central cannabinoid CB1 receptors  A major obstacle for the medical use of cannabis and cannabis-based medicines is the concern of their CB1 receptor mediated psychoactive effects, abuse liability and the long term use of such medications.
  60. 60.  CB2 receptors are also located in the brain microglia, particularly under some pathological conditions (e.g., neuroinflammation and injury);  microglia plays key role in the process of chronic pain called “central sensitization” and the presence of CB2 receptors indicate role of CB2 receptors in chronic (inflammatory and neuropathic) pain.  data suggest that CB2 receptor agonists are effective for decreasing persistent chronic (inflammatory and neuropathic) pain with low abuse liability and represents a potential drug target for pain treatment.
  61. 61.  Sativex, a buccal formulation (sublingual spray) of cannabis extract with fixed 1:1 ratios of Δ9-tetrahydrocannabinol and cannabidiol, produced analgesia in chronic, neuropathic pain conditions and multiple sclerosis.  This new formulation is in phase III clinical trials for multiple sclerosis patients in the UK and has been granted approval in Canada for the symptomatic relief of neuropathic pain in multiple sclerosis.
  62. 62.  the inhibitory neurons in the spinal cord dorsal horn control the transmission of “pain” signals from the periphery to higher levels of the brain where pain sensation is perceived  γ- aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the spinal dorsal horn  GABAA receptor agonists have antinociceptive activities in experimental models of pain  GABAA receptor is a heteropentameric chloride channel that comprises two α (α1, α2, α3 or α5) subunits, two β subunits and one γ2 subunit
  63. 63.  functionality of the different α subunits:  α1 subunits are primarily involved in the sedative effects  α2/α3 subunits are involved in anxiolytic and spinal antihyperalgesic effects of benzodiazepines  it is possible to develop subtype selective ligands targeting α2/α3 subunits of GABAA receptors as potential analgesics, which may be devoid of the untoward effects such as sedation and abuse liability.  Subtype-selective GABAA receptor positive modulators may represent a novel class of analgesics for the treatment of chronic pain.
  64. 64.  I2 receptor agonists are effective for alleviating acute visceral, inflammatory and neuropathic pain.  In addition, I2 receptor agonists synergically increase the antinociceptive effects of opioids and blunt the development of opioid tolerance.  This makes I2 receptors an attractive drug target for the development of analgesics and analgesic adjuncts.
  65. 65.  Many treatment modalities are being used to reduce and alleviate pain.  However, many clinical questions are still unanswered attributed to the complexity of the process involved  The research and treatments in the field of pain management are in the early stages of development, with many unmet goals.  Currently there are several promising novel drug targets available and numerous new chemical entities under development.  In the coming years, several advances are expected in the basic and clinical sciences of pain, which will provide improved new therapies for patients.

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