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