Download - Recent advances in Pain Management
Recent Advances in Pain Management
As we go along History
Pain pathophysiology
Pharmacotherapy
Opioids
NMDA receptor antagonist
NSAIDS
Antidepressants
Anticonvulsants
Topical agents
PCA
• The opium poppy is cultivated in lower Mesopotamia
460 B.C Hippocrates- magical attributes of opium but
acknowledges its usefulness as a narcotic .
• 1500 -The Portuguese- initiate the smoking of opium.
• 1803-Friedrich Sertürner of Paderborn, Germany - alkaloids
- Principium somniferum or morphine.
• 1841 -The Chinese are defeated by the British in the
First Opium War.
• 1895 Heinrich Dreser working for The Bayer Company of
Elberfeld "heroin would not be introduced commercially
•
“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.”
International Association for the Study of Pain, 1979
Pain is whatever the experiencing person says it is, existing whenever
he/she says it does.”
Margo McCaffery, 1999
Types of Pain
1. Acute (< 6 months)
2. Chronic (6 months <)
Somatogenic pain is pain with cause (usually known) localised in the body
nociceptive pain neuropatic pain
Psychogenic pain is pain for which there is no known physical cause but processing of sensitive information in CNS is disturbed
Acute
• Often obvious distress
• Sharp, dull, shock-like, tingling, shooting, radiation, fluctuating in intensity, and varying in location
• Occur in timely relationship to noxious stimuli
• May see HTN, increased HR, diaphoresis, pallor…
Chronic
• Appear to have no noticeable suffering
• Can be dull, shock-like, tingling, radiation, fluctuating in intensity, and varying in location
• Do NOT occur in timely relationship to noxious stimuli
• Symptoms may change over time
• Usually NO obvious signs
Acute Pain (Nociceptive)
Nociceptors
–specialised sensory receptors responsible for the
–detection of noxious stimuli
–transforming the stimuli into electrical signal.
Aβ fibres -myelinated and of large diameter, allowing rapid signal conduction
Aδ fibres - lightly myelinated conduct more slowly than Aβ fibres.mechanical and thermal stimuli. Rapid, sharp pain. Initial reflex response to acute pain
C fibres -unmyelinated , smallest type of primary afferent fibre.slowest conduction. slow, burning pain.
Nucleus Raphe magnusRostroventral medulla
LC-NE
The main pain gates are:
1- Spinal gate: at the SG.
2- Brain stem gate: at the nuclei of reticular formation.
3- Thalamic gate:
At neurons of PVLNT & intalaminar thalamic nuclei.
3
1
2
Gate control theoryNociceptive impulses Spinal cord
• Large A- delta and small C- fibers
• These fibers create synapses in the SG .The cells in this structure function
as a gate "open the gate". • Transmission of impulses to CNS
Stimulation of larger nerve fibers (A-alfa, A-beta)
• The cells in SG to "close the gate".
• A closed gate decreases stimulation of T-cells decreases transmission of
impulses
Sites of Action Medications
Peripherally (at the nociceptor)
Cannabinoids, NSAIDs, Opioids, Tramadol, Vanilloid receptor antagonists(i.e., capsaicin)
Peripherally Local anesthetics,
(along the nociceptive nerve)
Anticonvulsants (except the gabapentinoids)
Centrally (various parts of the brain)
Acetaminophen Anticonvulsants (except the gabapentinoids), Cannabinoids. Opioids, Tramadol
Descending Inhibitory pathway in the spinal cord
Cannabinoids, Opioids, Tramadol, Tricyclic antidepressants, SNRIs
Dorsal horn of the spinal cord
Anticonvulsants, Cannabinoids, Gabapentinoids, NMDA receptor antagonists, Opioids,. Tramadol, Tricyclic
antidepressants, SNRIs
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 3Opioid for moderate to severe pain
Nonopioid Adjuvant
Invasive treatments Opioid Delivery
Quality of Life
Modified WHO 3- Step Analgesic Ladder
Proposed 4th Step
The WHOLadder
Deer, et al., 1999
8 -10
4 - 7
1 - 3
Pain Severity
Opioids-classification• Natural opium alkaloids: Morphine, codeine
• Semisynthetic opiates: Hydromorphine,oxycodone,hydrocodone,oxymorphone
• Synthetic opioids: Pethidine, fentanyl, methadone, dextropropoxyphene, tramadol.
Complex action opioids & opioid antagonists:
• Agonist-antagonist: (κ-analgesics)
Nalorphine, pentazocine, butorphanol
• Partial/weak µ-agonist + κ-antagonist: Buprenorphine
OpioidsDecember 1804 in Paderborn, Germany,by Friedrich Sertürner.
Sertürner and Company in 1817 as an analgesic,
Commercial production began in Darmstadt, Germany in 1827.
Endogenous Opoid PeptidesOPIOID
RECEPTOR CLASS
EFFECTSASSOCIATED ENDOGENOUS
ENDORPHIN
Mu 1Euphoria, supraspinal analgesia, confusion, dizziness, nausea, low addiction potential
Endormorphin 1,2
Mu 2Respiratory depression, CV and GI effects, miosis, urinary retention
Beta-endorphin
DeltaSpinal analgesia,Opioid renforcement CV depression, decreased brain and myocardial oxygen Demand
Enkephalin
Kappa
Supraspinal,Spinal ,Peripheral analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system
Dynorphin A, beta-endorphin
Nociceptin/orphanin
Nociceptin peptide is present in neurons widely distributed throughout brain and
spinal cord structures.
Endomorphins
endomorphin-1 and endomorphin-2
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
•Supraspinal•Spinal•Perpheral
Analgesic action
Cortical areas
Supraspinal Analgesia
Strong analgesic
Dull continuous pain is relieved more effectively
than sharp shooting pain.
Action on Cingulate gyrus, para hippocampal
region & limbic system – Mood changes, euphoria,
tranquility, mental clouding, drowsiness,
indifference to surroundings as well as to our body
Pharmacokinetics
• Modestly absorbed from the GI tract
t1/2 of morphine is ~2 hours.
• Morphine-6-glucuronide
• Excreted by the kidney
• Satisfactory analgesia in cancer patients is associated with a very broad
range of steady-state concentrations of morphine in plasma (16-364 ng)
POTENTANALGESIC
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 timeFDA approval
2014!!
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• –Variable bioavailability
DepoFoam™Particle(diameter: 15 microns)
The non-concentric vesicles are surrounded by a lipid
membrane, and each contains an internal aqueous
chamber with morphine sulfate solution
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
Fentanyl and Congeners
• Synthetic opioid related to the phenylpiperidines
• Extremely potent analgesics
• Very short duration of action
SufentanilRemifentanilAlfentanil
Pharmacological action
• Rigidity
• Respiratory depression the onset is more rapid.
• Delayed respiratory depression also can be seen.
• Neuroexcitation
• Decrease heart rate and mildly decrease blood pressure.
• Do not release histamine
• No direct depressant effects on the myocardium are minimal
Pharmacokinetics
• Highly lipid soluble and rapidly cross the blood-brain barrier.
• t1/2, 3-4 hours. Fentanyl and sufentanil
• Hepatic metabolism and renal excretion.
• Higher doses/ prolonged infusions- these clearance mechanisms become
progressively saturated
RAMIFENTANYL
t1/2 of 8-20 minutes
metabolized by plasma esterases
Elimination is independent of hepatic metabolism or renal
excretion
Remifentanil acid, has 0.05-0.025% of the potency of the
parent compound, and is excreted renally.
Therapeutic Uses
• Fentanyl is ~100 times more potent than morphine
• sufentanil is ~1000 times more potent than morphine.
• The time to peak analgesic effect after iv- fentanyl and sufentanil (~5 minutes)
• Transdermal patches - sustained release of fentanyl for 48-72hrs
• Trans buccal absorption by the use of buccal tablets, soluble buccal film, and
lollypop-like lozenges permits rapid absorption
1. Postoperative pain has been popular2.Labor analgesia3.Chronic pain treatment
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
Contd(Ramifentanil)..• Short, painful procedures that require intense analgesia and
blunting of stress responses
• Continuous IV infusion
• Short duration of action makes bolus administration impractical
• Longer neurosurgical procedures
• Postprocedural analgesia- remifentanil + longer-acting
opioid or another analgesic modality is combined
• Remifentanil is not used intraspinally
Meperidine
• Synthetic opioid.
• Biotransformed by liver to Normeperidine, it is potentially neurotoxic
metabolite.
• Half life is 3 hr.
• Repetetive dosing causes accumulation of normeperidine which precipitate
tremulousness, myoclonus & Seizures.
• C/I in patients receiving Monoamine oxidase inhibitors as it precipitate a
syndrome characterised by muscle rigidity, hyperpyrexia & seizures
Methadone Synthetic opioid. Long acting MOR.Broad spectrum opioid-
• µ receptor agonist.
• NMDA antagonist.
• Inhibitors of Monoamine transmitter reuptake.
It has exactly identical pharmacodynamics as that of Morphine in equi-analgesic doses.
Opioid rotation is very useful technique to restore analgesic sensitivity in highly tolerant
patient.
2.5-10 mg repeated every 8-12 hours Tab/IM/SC
Neuropathic pain- chronic pain
Methadone is a choice for opioid rotation
Absorbed well from the GI tract
Extensive biotransformation in
the liver
Excreted in the urine
t1/2 15-40 hours
L-Methadone
Buprenorphine
• Potent semisynthetic opioid.
• Not related to Morphine but to Thebaine.
• 50 times greater affinity than that of Morphine.
• Respiratory depression is prolonged..
• t1/2 in plasma is ~3 hours. Metabolized to norbuprenorphine by CYP3A4.
• Indicated in cancer pain, Opioid dependence
• Oral/IM/Sublingual./IM/IV Sublingually-0.4-0.8 mg- postoperative patient
Also available transdermally as 35, 52.5, and 70 µg/h transdermal
patches that deliver the dose over 96 hours.
BuprenorphineOpioid
Empty Receptor
Withdrawal Pain
Opioid Receptor in the brain
0.4 mg buprenorphine
= 10 mg morphine IM
)
2001
2000
Pentazocine• κ1 agonist
• Produces Spinal level analgesics• Sedation, drowsiness & respiratory depression. Due to σ stimulation it
causes – Dysphoria, hallucinations, diaphoresis & psychotomimetic effects– Increases BP/ HR/ pulmonary artery pressureIndicated in post operative pain, moderately severe pain in burns,
trauma, fractures etc
Tablets available in fixed-dose combinations with acetaminophen or
naloxone
Combination - the potential misuse of tablets as a source of injectable
pentazocine by producing undesirable effects in subjects dependent on
opioids.
weak antagonist or partial agonist at opioid receptors.
APPROXIMATE
EQUI-ANALGESICAPPROXIMATE
EQUI-ANALGESICRECOMMENDED STARTING DOSE
(adults > 50 kg)
DRUG ORAL DOSE PARENTERAL DOSE ORAL PARENTERALOpioid Agnoists
Morphineb
30 mg q3-4h (around-the-clock dosing) 60
mg q3-4h (single dose or intermittent dosing)
10 mg q3-4h 15 mg q3-4h 5 mg q3-4h
Codeinec 130 mg q3-4h 75 mg q3-4h 30 mg q3-4h 30 mg q2h (1M/SC)
Hydrocodone (DILAUDIO)b 7.5 mg q3-4h 1.5 mg q3-4h 4 mg q3-4h 1 mg q3-4h
Hydrocodone (in LORCET, LORTAB, VICODIN, others,
typically with acetominophen)30 mg q3-4h Not available 5 mg q3-4h Not available
Levorphanol 4 mg q6-8h 2 mg q6-8h 2 mg q3-4h 1 mg q6-8h
Meperidine (DEMEROL) 300 mg q2-3h 100 mg q3h Not recommended 50 mg q3hMethadone (DOLOPHINE,
others) 20 mg q6-8h 10 mg q6-8h 2.5 mg q12h 2.5 mg q12h
Oxycodone (REXICODONE, OXYCONTIN, also in PECOCET, PERCODAN, TYLOX, others)g
30 mg q3-4h Not available 5 mg q3-4h Not available
Oxymorphoneb (NUMORPHAN) Not available 1 mg q3-4h Not available 1 mg q3-4h
Propoxyphene (DARVON) 130 mge Not available 65 mg q4-6he Not available
Tramadolf (ULTRAM) 100 mge 100 mg 50-100 mg q6he 50-100 mg q6he
Adverse Effects of the Opioid AnalgesicsBehavioral restlessness, tremulousness, hyperactivity (in dysphoric reactions)
Respiratory depression
Nausea and vomiting
Increased intracranial pressure
Postural hypotension accentuated by hypovolemia
Constipation
Urinary retention
Itching around nose, urticaria (more frequent with parenteral and spinal administration)
Degrees of Tolerance that may develop to some of the effects of the Opioids
High Moderate Minimal or NoneAnalgesia Bradycardia Miosis
Euphoria, dysphoria Constipation
Mental clouding Convulsions
Sedation
Respiratory depression
Antidiuresis
Nausea and vomiting
Cough suppression
Precautions
• Integrity of the blood-brain barrier
• Caution in patients with hepatic disease/renal diseases
• Compromised respiratory function
• Elevated intracranial pressure
• History of asthma
• Anaphylactoid reactions
• Synthetic codeine analog. Weak MOR agonist
1. Produces antinociception via predominantly, a mu-opioid receptor mechanism.
2. No respiratory depression, sedation, or constipation, as observed with other
opiates.
3. No analgesic tolerance
4. No psychological dependence or euphoric effects in long-term clinical trials
1. Novel mechanism of analgesic action is partially due to
its adrenergic action
2. Enhanced secretion of serotonin and inhibits the
reuptake of serotonin in the CNS
OPIOD ACTIVITY
Monoaminergic Activity
Pharmacokinetics1. Effective and well-tolerated analgesic in all 3 forms of administration
2. PO,IV,PR
3. Onset of analgesia is within 30 minutes.
4. Duration of action from 3 to 7 hours
5. Drowsiness - most frequent side effect
6. Transformation by the cytochrome P450 complex to the metabolically active
O-desmethyl-tramadol
Withdrawal symptoms after abrupt discontinuation or reduction of dose
DependenceSerotonin Syndrome
Tapendalol
1. FDA approved
tapentadol in
2008
2. moderate-to-
severe acute pain
in patients older
than 18 years
NMDA antagonists
• Memantine• Amantadine• Ketamine
Indications
• Windup pain
• Opioid tolerance
• Opioid induced hyperalgesia
• Receptive field size increase
• Pain threshhold reduction
• Longterm potentiation
Pharmacokinetics
• Absorbed completely from the gastrointestinal tract
• The protein binding is 42% to 45%.
• Elimination mainly by kidneys as unchanged substance as well as its
hydroxylated metabolites.
• Memantine crosses the blood-brain barrier
• Maintenance doses of 20 mg/day- tablet and solution
• Most common side effects include constipation, confusion, dizziness,
headache, hallucinations, coughing, and hypertension
• Magnesium-• Initial Bolus of 30-50 mg/kg. • Infusion in surgeyr (600 – 700 mg/hr
• AMANTADINE• IV 200mg infused over 3 hours
Decreased Postop shivering
Improved postop sleep quality
Decreased airway irritability
Prevents succinylcholine myalgias
Decreased sympathetic responses
Improved skeletal muscle relaxation
Bronchodilitation
KETAMINE INFUSION
A congener of phencyclidine
Non-competitive glutamate NMDA
receptor antagonist.
• At low doses, the analgesia effects of ketamine are mediated by
antagonism on the NMDA receptors.
• Evidence for this is reinforced by the fact that naloxene, an opioid
antagonist
Therapeutic uses
Management of moderate to severe pain.
• Used in conjunction with opioids
• 10-, 50 and 100-mg/mL solutions in sodium chloride plus the preservative
benzethonium chloride.– Sedation/Analgesia IV: 0.5 – 1.0 mg/ IM/ rectal: 2.5 – 5.0 mg/kg PO: 5 – 6
mg/kg– Norketamine, rapid clearance, large Vd
Paracetamol, opioids, local anaesthetics, tramadol and NSAIDs may be used
concurrently with ketamine infusions
improve analgesia and reduce side effects.
The ketamine-induced cataleptic state -nystagmus with
pupillary dilation, salivation, lacrimation.
NSAIDS AND COX INHIBITORS
INHIBITION OF CHEMOTAXISDOWN-REG. OF IL-1 PROD. DECREASED PRODUCTION OF FREE RADICALS AND SUPEROXIDE, INTERFERENCE WITH CALCIUM-MED. INTRACELLULAR EVENTS
• NON – SELECTIVE REVERSIBLE INHIBITORS OF COX
• Indomethacin, ibuprofen, ketoprofen , sulindac,naproxen,piroxicam ,ketorolac,tolmeti
n, diclofenac, aceclofenac
• Acetaminophen raises the threshold to painful stimuli, thus
exerting an analgesic effect against pain due to a variety of
etiologies.
• Oral acetaminophen has excellent bioavailability
• t1/2 in plasma is 2 hours.Hepatic conjugation with glucuronic acid
•In 2009, FDA a recommended a maximum daily dose of 2600 mg •Decrease in the maximum single dose from 1000 mg to 650 mg.
NAPQI, a highly reactive intermediate
• Doses of acetaminophen in combination
opioid/NSAID –
• Adjusted to the patient's body weight.
• Maximum acetaminophen dose:
• 4 g/day in adults, 90 mg/kg/day in children.
• Doses for moderate pain not necessarily equivalent
to 30 mg oral or 10 mg parenteral morphine
Intravenous Paracetamol
Adv:Propacetamolreduces 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!!!
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.
Potential pharmacological targets under research and clinical trials
Licofelone
• Dual 5-LOX / COX inhibitor
• Anti-inflammatory, analgesic, anti-pyretic, anti-asthmatic, reduces
LTB4 production (decreases NSAID-induced gastrotoxicity),
decrease cartilage degradation
• Phase lll trial
• No known CVS, CNS toxicity
Antidepressants
• Tricyclic antideprassants
• SNRI’s
Antidepressants• Multiple mechanisms of action
• RCTs and meta-analyses demonstrate benefit of tricyclic
antidepressants especially amitriptyline, imipramine
Postherpetic neuralgia 30-150mg/day
• Diabetic neuropathy
Onset of analgesia variable
– analgesic effects independent of antidepressant activity
• Improvements in insomnia, anxiety, depression
NOT FDA APPROVED!!!
Duloxetine
• Selective serotonin norepinephrine reuptake inhibitor (SNRI)
• Central pain inhibitory actions-
Balanced activity as an inhibitor of 5-HT and NE reuptake with very low activity on dopamine reuptake
Pharmacokinetics
• Well absorbed orally. t ½ = 10 hrs
• undergoes extensive hepatic metabolism to inactive compounds
• highly bound to plasma proteins.
• Excreted unchanged in the urine.
• 30 mg once daily Increase to 60 mg once
• daily after one week
• 60 mg twice daily 4 weeks
Peripheral Neuropathy
Venlafaxine• Low doses (<150 mg/day)-serotonergic transmission.
• Moderate doses (>150 mg/day)-serotonergic and noradrenergic systems
• High doses (>300 mg/day)- dopaminergic neurotransmission
• Extensively metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine
• Therapeutic effects are usually achieved within 3 to 4 weeks
• Black box warning with a generic warning about a possible suicide risk,withdrawal
symptoms,seritonon syndrome
• ER TABLETS-150–225 mg DIABETIC NEUROPATHY
Black box warning with a generic warning about a possible suicide
risk,withdrawal symptoms,seritonon syndrome
ANTICONVULSANTS
Carbamazepine 100mg BD ( to 400mgbd/tds)
Valproate 200mg BD ( to 1000-2000mg/d)
Phenytoin 100mg nocte ( to 500mg/d)
Gabapentin 3,600 mg/d (tid–qid)
Pregabalin 300 mg/day
Lamotrigine 250mg/day
Leveteracetam 1500mg bd
Anticonvulsant Drugs for Neuropathic Pain Disorders
• Postherpetic neuralgia– gabapentin– pregabalin
• Diabetic neuropathy– carbamazepine– phenytoin– gabapentin– lamotrigine– pregabalin *
• HIV-associated neuropathy – lamotrigine
• Trigeminal neuralgia– carbamazepine– lamotrigine– oxcarbazepine
• Central poststroke pain– lamotrigine
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
Neuropathic pain
Diabetic Neuropathy DuloxetineGabapentinPregabalinTCAVenlafaxine ER
OpioidsTramadol*
Post Herpetic Neuropathy GabapentinPregabalinTCALidocaine plasters
CapsaicinOpioids
Trigeminal Neuropathy CarbamazepineOxcarbazepine
Surgery
Central pain--eg. MS, CPSP, SCI
GabapentinPregabalinTCA (Amitriptyline)
Cannabinoids (MS)Lamotrigine (CPSP)OpioidsTramadol (SCI)
Muscle pain Myofassial pain syndrome (neck, shoulders, arms, low back, hips and lower extremities)
TCA (Amitryptiline)CyclobenzaprineMuscle relaxants
Opioids
Inflammatory pain Inflammatory arthropathies (rheumatoid arthritis)InfectionPostoperative painTissue injury
NSAIDsIntra-articular corticosteroidsTCAcyclobenzaprine
Systemic corticosteroidsBiologic response modifiers opioids rarely needed
Mechanical/compressive pain Low back painNeck pain, Musculoskeletal pain
NSAIDsTCA
Opioids rarely needed Surgery
Gabapentin Pregabalin
Carbamazepine Oxcarbazepine
TCA SNRI
Side effects SedationAtaxiaDizzinessMental changeMemory problemHeadacheWeight gainOedemaFlatulence
SedationAtaxiaDizzinessMental changeMemory problemHeadacheWeight gainOedemaHyponatraemia
SedationDizzinessMental changeWeight gainDry mouthHypotensionSweatingPalpitationsConstipationBlurred vision
SedationDizzinessMental changeNauseaWeight lossHypertensionSweatingDiarrhoea
Contradictions None? AV-blockPorphyriaMAO inhibitors
AV-blockCardiac insufficiencyRecent MIMAO inhibitors
Liver function Kidney functionMAO inhibitors
Ziconotide
• Highly hydrophilic • conopeptide ω-MVIIA from the venom of the Pacific fish-hunting snail
IT
Clearance from the cerebrospinal fluid
half-life 4-6hrs
Transport into the systemic circulation
Degraded by peptidases and proteases
Non-progressiverises in serum concentrations of creatine
kinase muscle isoenzyme (CK-MM)
Intrathecal catheter-associated complications
Dizziness,confusion, ataxia,abnormal gait ,memory
impairment
• Approved as intrathecal monotherapy.
• Severe chronic pain, refractory pain
• 25 μg/mL or 100 μg/mL. Dilution, if needed, should be done
aseptically with preservative-free sodium chloride (0 ・ 9%) solution
TOPICAL
• Lidocaine
• Capsacian
Lidocaine 5%• Pliable patch
• Up to 3 patches applied once daily directly over
painful site
– 12 h on, 12 h off (FDA-approved label)
– recently published data indicate 4 patches (18–24 h) safe
• Efficacy demonstrated in 3 randomized controlled trials on postherpetic
neuralgia
Most common side effect: application-site sensitivity
• Clinically insignificant serum lidocaine levels
• Mechanical barrier decreases allodynia
• Topical Lidocaine patch
Peripheral tissue activity
Applied directly over painful
site
Insignificant serum levels
Systemic side effects unlikely
Capsacian• Capsaicinoids first recorded use, in the form of chilies, for the treatment of pain
dates back to 4000 BC
• 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.
• TRPV1 antagonists
– ABT-102
– TRPV1 antagonists have been developed and investigated as potential
options for the treatment of pain
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 workonset 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
Pharmacokinetics
Highly lipid soluble
Enters tissues rapidly
Oral/Rectal /IV/Smoking/
Metabolised in the liver. Excreted in the urine and
feces.
IV-- very low water solubility, requires special formulation Rapid onset of action- dosage limitations short duration of effect
Smoking - rapid absorption (like IV)- bioavailability 18-50%- high variability due to smoking
techniques
Topical - very limited applicability
• Levonantradol is a synthetic analogue of THC that is administered IM-palliate postoperative pain or pain due to trauma
• Cannabidiol (CBD)
• Dronabinol
• Nabilone
Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders
Disorder Target Symptoms Therapeutic Cannabinoid Clinical Outcome
Multiple Sclerosis Spasticity Oral THC, CBD In progress
Neurogenic pain Sublingual THC, CBD Phase II trial in progress
Bladder dysfunction Sublingual THC, CBD Phase II trial in progress
Parkinson's disease Dystonia Nabilone No effect
Dyskinesia Nabilone Lowers dyskinesia
Tremor Δ9 - THC No effect
Cancer Pain Sublingual THC, CBD Phase III trial in progress
Postoperative pain Pain IM levonantradolReduces pain, but less effective than existing therapies
Disorder Target Symptoms Therapeutic Cannabinoid Clinical Outcome
Spinal cord injury Pain Sublingual THC, CBD Phase II trial in progress
GI tract pain Pain THC Lowers Morphine requirement
Traumatic Brain Injury/Stroke Neurodegeneration IV dexanabinol (HU-211)Lowers intracranial pressure,lowers mortality, phase III trial in progress
Neurodegeneration CBD In progress
HIV wasting syndrome Appetite loss, nausea Smoked cannbis In progress
Appetite loss, nausea DronabinolIncreases appetite, decreases nausea
Tourette's syndrome Behavioural disorders THC Undetermined
Therapeutic uses
Fibromyalgia- 0.5 mg hs and
increasing weekly up to 1 mg BID
Chronic non-cancer pain (CNCP)-
Nabilone (0.5 mg hs to 2.0 mg BID
Neuropathic pain- 2mg BD
C/I: previous adverse cannabis/cannabinoid reactions excessive use of benzodiazepines, barbiturates, alcohol
Ibudilast• Ibudilast is a non-selective phosphodiesterase inhibitor that suppress
glial cell activation
• platelet aggregation
• its ability to improve cerebral blood flow
• Anti iflammatory properties
• 10-mg capsules in Japan and other Asian countries for > 15 years for
BA and complications after cerebral infarction.
• Increased liver enzyme levels , anorexia, nausea
• Rare cases of thrombocytopenia were also reported.
Patient Controlled Analgesia (PCA)
PCA
• Management of moderate to severe pain
• inadequate analgesia would result from oral analgesia or intermittent IV
morphine boluses
• Morphine is the preferred opioid in most circumstances.
• Fentanyl or hydromorphone are alternative choices.
• Pethidine is NOT routinely used due to the concern for nor-pethidine toxicity
One hr max dose
Max amount of drug that PCA pump will deliver in 1 hour
Continuous infusion
Morphine 0.075 mg/kg lbw
Fentanyl 0.75 mcg/kg lbw
Increase PCA dose by ~25%
Consider adding a continuous infusion
Divide average hourly use by 2 to estimate new PCA dose
Relative Risk Factors associated with the use of patient-controlled analgesia
• Pulmonary disease
• Obstructive sleep apnea
• Renal or hepatic dysfunction
• Congestive heart failure
• Closed head injury
• Altered mental status
• Lactating mothers
Patient Controlled Epidural Analgesia Allows individualization of postoperative analgesic requirements
lower drug use and greater patient satisfaction.
provide analgesia superior to that afforded by intravenous PCA.
safe and effective technique for postoperative analgesia on routine
surgical wards
PCEA than with intravenous PCA and may provide analgesia superior
Addition of an opioid to the local anesthetic can provide superior analgesia
A lipophilic opioid is usually chosen because its rapid analgesic effect and
shorter duration of action may be more suitable for use with PCEA.
Patient-Controlled Epidural Analgesia Regimens
Analgesic SolutionContinuous Rate
(mL/hr)Demand Dose
(mL)Lockout Interval
(min)
General Regimens
0.05% bupivacaine + 4 µg/mL fentanyl 4 2 10
0.0625% bupivacaine + 5 µg/mL fentanyl 4 to 6 3 to 4 10 to 15
0.1% bupivacaine + 5 µg/mL fentanyl 6 2 10 to 15
0.2% ropivacaine + 5 µg/mL fentanyl 5 2 20
Thoracic Surgery
0.0625% - 0.125% bupivacaine + 5 µg/mL fentanyl 3 to 4 2 to 3 10 to 15
Abdominal Surgery
0.0625% bupivacaine + 5 µg/mL fentanyl 4 to 6 3 to 4 10 to 15
0.125% bupivacaine + 0.5 µg/mL fentanyl 3 to 5 2 to 3 12
0.1% - 0.2% ropivacaine + 2 µg/mL fentanyl 3 to 5 2 to 5 10 to 20
Lower Extremity Surgery
0.0625% - 0.125% bupivacaine + 5 µg/mL fentanyl 4 to 6 3 to 4 10 to 15
0.125% levobupivacaine + 4 µg/mL fentanyl 4 2 10
Continuous peripheral nerve block
New opiorphin analogs for chronic pain treatment
• Human opiorphin QRFSR-peptide protects enkephalins from degradation by
human neutral endopeptidase (hNEP) aminopeptidase-N (hAP-N)
• Inhibits pain perception in a behavioral model of mechanical acute pain
• Activates restricted opioid pathways specifically involved in pain control
contributing to a greater balance between analgesia and side-effects than
found with morphine
• Opiorphin could give rise to new analgesics with fewer adverse effects than
opioid agonists
Non-pharmacologic Pain Management
• Cognitive therapies (relaxation,
imagery, hypnosis)
• Biofeedback
• Behavior therapy
• Psychotherapy
• Complementary tx
• Massage therapy
• Art therapy
• Music therapy
• Aroma therapy
• Neurostimulation
• TENS
• Acupuncture
• Anesthesiology
• Nerve block
• Surgery
• Physical therapy
• Exercise
• Heat/cold
• Psychological approaches
Spinal cord stimulation
• Technology advances
• Systematic review
– 67% overall had >50% pain reduction > 6mths
– Effective in PHN (82%), limb ischaemia(77%), peripheral
neuropathy (67%).
DEEP BRAIN STIMULATION
• Meta-analysis 1966-2003 (Jan)
• PAG-PVG +sensory thalamus/internal capsule 79-87%
• DBS effective for nociceptivepain, FBSS, less so for neuropathicpain
• Invasive procedure
Transcranial magnetic stimulation
Mechanism due to
• inhibition of limbic system -secondary activation of pain and mood regulating
regions egcingulategyrus, insula, hippocampus
• Prefrontal rTMS
• Facial pain, FMS, post-gastric bypass
• Motor cortex rTMS
• Botulinum toxin: low back pain
• Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related
neuropathy, with gabapentin
• CR oxycodone: diabetic neuropathy
• Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others
• Levetiracetam: neuropathic pain and migraine
• Oxcarbazepine: neuropathic pain; diabetic neuropathy
• Bupropion: neuropathic pain
• Transdermal fentanyl: low back pain