Recent advances in Pain Management

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Information about Recent advances in Pain Management

Published on March 7, 2014

Author: rachanarajgopal


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. 2. Acute (< 6 months) 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 Chronic • Often obvious distress • Appear to have no noticeable suffering • Sharp, dull, shock-like, tingling, shooting, radiation, fluctuating in intensity, and varying in location • Can be dull, shock-like, tingling, radiation, fluctuating in intensity, and varying in location Occur in timely relationship to noxious stimuli • Do NOT occur in timely relationship to noxious stimuli May see HTN, increased HR, diaphoresis, pallor… • Symptoms time • Usually NO obvious signs • • may change over

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.

Increased Sympathetic Tone • Vasoconstriction producing increased peripheral resistance • Increased stroke volume and heart rate • Increased blood pressure • Increased metabolic rate and oxygen consumption • Decreased gastric tone (delayed gastric emptying; can progress to ileus) • Decreased urinary tract tone (leads to urinary retention Endocrine Responses • Decreased insulin production • Increased cortisol • Increased antidiuretic hormone • Increased growth hormone • Increased renin, angiotensin II, aldosterone • Increased glucagons • Increased catecholamines Respiratory Responses • Hyperventilation Cortical Responses • Anxiety and fear

Nucleus Raphe magnus Rostroventral medulla LC-NE

3 The main pain gates are: 1- Spinal gate: at the SG. 2- Brain stem gate: at the nuclei of reticular formation. 2 3- Thalamic gate: At neurons of PVLNT & intalaminar thalamic nuclei. 1

Gate control theory Nociceptive 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 Cannabinoids, NSAIDs, Opioids, Tramadol, Vanilloid receptor antagonists(i.e., capsaicin) (at the nociceptor) Peripherally Local anesthetics, Anticonvulsants (except the gabapentinoids) (along the nociceptive nerve) 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

Modified WHO 3- Step Analgesic Ladder Quality of Life Proposed 4th Step Invasive treatments Pain Severity Opioid Delivery Pain persisting or increasing Step 3 Opioid for moderate to severe pain Nonopioid Adjuvant 8 -10 Pain persisting or increasing The WHO Ladder Step 2 Opioid for mild to moderate pain Short acting opoid Adjuvant 4-7 Pain persisting or increasing Step 1 Nonopioid Adjuvant Pain Deer, et al., 1999 1-3

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

Opioids December 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 Peptides OPIOID RECEPTOR CLASS EFFECTS ASSOCIATED ENDOGENOUS ENDORPHIN Mu 1 Euphoria, supraspinal analgesia, confusion, dizziness, nausea, low addiction potential Endormorphin 1,2 Mu 2 Respiratory depression, CV and GI effects, miosis, urinary retention Beta-endorphin Delta Spinal analgesia,Opioid renforcement CV depression, decreased brain and Enkephalin myocardial oxygen Demand 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

•Inhibition of adenylyl cyclase activity •Reduced opening of voltage-gated Ca2+ channels Intracellular mechanism 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 POTENT ANALGESIC • 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)

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

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 The non-concentric vesicles are surrounded by a lipid membrane, and each contains an internal aqueous chamber with morphine sulfate solution DepoFoam™Particle(diamete r: 15 microns)

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 Sufentanil Remifentanil Alfentanil

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) 1. Postoperative pain has been popular 2.Labor analgesia 3.Chronic pain treatment • 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

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. L-Methadone • NMDA antagonist. • Inhibitors of Monoamine transmitter reuptake.  It has exactly identical pharmacodynamics as that of Morphine in equianalgesic 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 Absorbed well from the GI tract Extensive biotransformation in the liver Neuropathic pain- chronic pain Excreted in the urine Methadone is a choice for opioid rotation t1/2 15-40 hours

) Buprenorphine Opioid Buprenorphine • Potent semisynthetic opioid. • Not related to Morphine but to Thebaine. Empty Receptor 0.4 mg buprenorphine = 10 mg morphine IM • 50 times greater affinity than that of Morphine. • Opioid Receptor in the brain Respiratory depression is prolonged.. • Withdrawal Pain 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 2000 Also available transdermally as 35, 52.5, and 70 µg/h transdermal patches that deliver the dose over 96 hours. 2001

Pentazocine weak antagonist or partial agonist at opioid receptors. • 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 pressure Indicated 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.

APPROXIMATE APPROXIMATE EQUI-ANALGESIC EQUI-ANALGESIC DRUG Opioid Agnoists RECOMMENDED STARTING DOSE (adults > 50 kg) ORAL DOSE PARENTERAL DOSE ORAL PARENTERAL Morphineb 30 mg q3-4h (aroundthe-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 q3h 20 mg q6-8h 10 mg q6-8h 2.5 mg q12h 2.5 mg q12h 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 Methadone (DOLOPHINE, others) Oxycodone (REXICODONE, OXYCONTIN, also in PECOCET, PERCODAN, TYLOX, others)g

Adverse Effects of the Opioid Analgesics Behavioral 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 None Analgesia Euphoria, dysphoria Mental clouding Sedation Respiratory depression Antidiuresis Nausea and vomiting Cough suppression Bradycardia Miosis Constipation Convulsions

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 OPIOD ACTIVITY 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 Monoaminergic Activity

Pharmacokinetics 1. 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 Serotonin Syndrome Dependence

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

Decreased Postop shivering • Magnesium• Initial Bolus of 30-50 mg/kg. • Infusion in surgeyr (600 – 700 mg/hr • AMANTADINE • IV 200mg infused over 3 hours 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. The ketamine-induced cataleptic state nystagmus with pupillary dilation, salivation, lacrimation. • 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.



• NON – SELECTIVE REVERSIBLE INHIBITORS OF COX • Indomethacin, ibuprofen, ketoprofen , sulindac,naproxen,piroxicam ,ketorolac,tolmetin, diclofenac, aceclofenac

• Acetaminophen raises the threshold to painful stimuli, thus exerting an analgesic effect against pain due to a variety of etiologies. NAPQI, a highly reactive intermediate • 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.

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

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 NOT FDA APPROVED!!! • 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

Duloxetine • Selective serotonin norepinephrine reuptake inhibitor (SNRI) • Central pain inhibitory actions- Balanced activity as an inhibitor of 5HT 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 Black box warning with a generic warning about a possible suicide symptoms,seritonon syndrome risk,withdrawal symptoms,seritonon syndrome • ER TABLETS-150–225 mg DIABETIC NEUROPATHY


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

Diabetic Neuropathy Duloxetine Gabapentin Pregabalin TCA Venlafaxine ER Opioids Tramadol* Post Herpetic Neuropathy Gabapentin Pregabalin TCA Lidocaine plasters Carbamazepine Oxcarbazepine Gabapentin Pregabalin TCA (Amitriptyline) Capsaicin Opioids TCA (Amitryptiline) Cyclobenzaprine Muscle relaxants Opioids NSAIDs Intra-articular corticosteroids TCA cyclobenzaprine Systemic corticosteroids Biologic response modifiers opioids rarely needed Neuropathic pain Trigeminal Neuropathy Central pain --eg. MS, CPSP, SCI Muscle pain Inflammatory pain Mechanical/compressive pain Myofassial pain syndrome (neck, shoulders, arms, low back, hips and lower extremities) Inflammatory arthropathies (rheumatoid arthritis) Infection Postoperative pain Tissue injury Low back pain NSAIDs Neck pain, Musculoskeletal pain TCA Surgery Cannabinoids (MS) Lamotrigine (CPSP) Opioids Tramadol (SCI) Opioids rarely needed Surgery

Gabapentin Pregabalin Side effects Carbamazepine Oxcarbazepine Sedation Ataxia Dizziness Mental change Memory problem Headache Weight gain Oedema Flatulence Contradictions None? TCA SNRI Sedation Ataxia Dizziness Mental change Memory problem Headache Weight gain Oedema Hyponatraemia Sedation Dizziness Mental change Weight gain Dry mouth Hypotension Sweating Palpitations Constipation Blurred vision Sedation Dizziness Mental change Nausea Weight loss Hypertension Sweating Diarrhoea AV-block Porphyria MAO inhibitors AV-block Cardiac insufficiency Recent MI MAO inhibitors Liver function Kidney function MAO 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 work onset of action faster with smoking Anandamide mimic THC • New water-soluble esters of THC-acid analogs – analgesic and anti-inflammatory action – no psychoactivity, no gastric irritation – possible replacement for NSAIDs?

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 Multiple Sclerosis Target Symptoms Therapeutic Cannabinoid Clinical Outcome 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 Dystonia Nabilone No effect Dyskinesia Nabilone Lowers dyskinesia Tremor Δ9 - THC No effect Cancer Pain Sublingual THC, CBD Postoperative pain Pain IM levonantradol Phase III trial in progress Reduces pain, but less effective than existing therapies Clinical Outcome Parkinson's disease Disorder Target Symptoms Therapeutic Cannabinoid Spinal cord injury Pain Sublingual THC, CBD Phase II trial in progress GI tract pain Pain THC Traumatic Brain Injury/Stroke Neurodegeneration IV dexanabinol (HU-211) Neurodegeneration CBD Lowers Morphine requirement Lowers intracranial pressure, lowers mortality, phase III trial in progress In progress Appetite loss, nausea Smoked cannbis Appetite loss, nausea Dronabinol Behavioural disorders THC HIV wasting syndrome Tourette's syndrome In progress Increases appetite, decreases nausea 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 Increase PCA dose by ~25% Continuous infusion Consider adding a continuous infusion Morphine 0.075 mg/kg lbw Fentanyl 0.75 mcg/kg lbw 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 Continuous Rate (mL/hr) Demand Dose (mL) Lockout Interval (min) 4 2 10 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 3 to 4 2 to 3 10 to 15 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 4 to 6 3 to 4 10 to 15 4 2 10 Analgesic Solution General Regimens 0.05% bupivacaine + 4 µg/mL fentanyl 0.0625% bupivacaine + 5 µg/mL fentanyl Thoracic Surgery 0.0625% - 0.125% bupivacaine + 5 µg/mL fentanyl Abdominal Surgery Lower Extremity Surgery 0.0625% - 0.125% bupivacaine + 5 µg/mL fentanyl 0.125% levobupivacaine + 4 µg/mL fentanyl

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 • • Neurostimulation • Cognitive therapies (relaxation, imagery, hypnosis) TENS • Biofeedback • Behavior therapy • Acupuncture • Anesthesiology • Psychotherapy • Nerve block • Complementary tx • Surgery • Massage therapy • Physical therapy • Art therapy • Exercise • Music therapy • Heat/cold • Aroma therapy • 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

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