Acute pain relief – recent drugs

Dr. S. Parthasarathy
MD, DA, DNB,
Dip Diab.MD , (ACU) Dip software based statistics,
PhD (physiology)
IDRA CUGRA
www.painfreepartha.com
My salute !!

Legendary teacher of two

centuries--
Dr. M.Ravishankar

03/07/2024
• See the big building

• But we need to understand the

foundation
We are using certain drugs
• Ibuprofen
• Ketoprofen
• Diclofenac
• Aceclofenac
• Ketoroloc

• What are the worries

• Stomach, bleeding and the kidney
So many drugs have come
and gone / stayed
 Lornoxicam
• Lornoxicam is a non-selective COX inhibitor.
• It is available in oral (4 mg and 8 mg film coated tablet
• (8 mg powder for injection).
• The dose is 8–16 mg per day in 2 to 3 divided doses,
• osteoarthritis (OA), post-surgery sciatica
• is an adjunct to opioids.
• Side effects include nausea and diarrhoea, headache, bronchospasm and
Stevens–Johnson syndrome.
• Less gastritis – can combine with paracetamol
• Less effective than 400 mg ibuprofen = my opinion
16 mg lornoxicam is very good !
The addition of lornoxicam to lidocaine for intravenous regional
anaesthesia shortens the onset of sensory and motor block, decreases
tourniquet pain and improves postoperative analgesia without causing
any side effect.
Meloxicam
• COX-2 selective NSAID.
• It is available in oral and parenteral formulations.
• The dose is 7.5 mg orally 12-hourly up to a maximum of 15 mg/day.

• It is used for pain and inflammation in rheumatoid arthritis (RA) and

OA.
• The side effects of using it include allergic reactions, especially in
patients with asthma, new onset or worsening high BP, oedema and
reduced kidney function.
Perioperative meloxicam IV 30 mg as part of a multimodal analgesic
regimen for elective primary TKA reduced opioid consumption in the
24-hour period after surgery versus placebo and was associated with a
lower incidence of all side effects associated with opioid use.
 preoperative meloxicam achieves better efficacy and
similar tolerance compared to postoperative meloxicam in
hip OA patients post THA. Minimal insignificant side
effects
Coxibs entered the fray
• As COX 2 inhibitors they had the potential to decrease pain without GI
side effects
• It shook the market 15 years ago
• I have used preemptive valdecoxib in lap chole and found very useful

• But probable increased incidence of atherosclerosis and worsening

strokes and heart attacks- some brakes on their use !
• CERTAIN COXIBS HAVE COME
OUT VICTORIUOS AFTER
HURDLES
Celecoxib
• available as an oral formulation (capsules, 50 mg, 100 mg, 200 mg,
400 mg). The usual dose for acute pain is 400 mg initially, then 200
mg 12-hourly as required.
• OA, RA, ankylosing spondylitis, acute pain, musculoskeletal pain and
painful menstruation. It is also used to reduce polyps in rectum and
colon in patients with familial adenomatous polyposis
• Same side effects -- Nausea, diarhea and GIT bleeds !
The administration of celecoxib is an effective and safe strategy
for postoperative analgesia after TKA.
Etoricoxib
• COX-2 specific NSAID. It is available as an oral formulation (30 mg, 60
mg, 90 mg, 120 mg film coated tablets). The dose in OA is 60 mg
daily,
• Administration of etoricoxib 2 h before surgery allows for an effective
drug concentration in critical tissues, a reduction of the production of
pro-inflammatory mediators and for better pain relief.

90 mg is enough to have good

pain relief
Even in other surgeries !
Nefopam
• Acute pain relief
• Some use in neuropathic component
• Decreases shivering

• Ideal perioperative use

• Possible neuropsychiatric complications have put the drug in question

Nefopam 0.3 mg/ kg before anaesthesia –
reduced periop morphine
Etodoloc
• Etodolac, a preferential COX-2 inhibitor, does not inhibit platelet
aggregation in a randomized placebo-controlled trial

• Worth thinking in the perioperative setting

Nabumetone
• Nabumetone is a nonacidic NSAID prodrug that is rapidly
metabolized in the liver to the active metabolite, 6-methoxy-2-
naphthyl acetic acid.
• As found with previous NSAIDs, nabumetone's active metabolite
inhibits the cyclooxygenase enzyme and preferentially blocks COX-2
activity (which is indirectly responsible for the production of
inflammation and pain during arthritis

• Less effect on stomach – less effect on kidneys

• Human studies on acute post operative pain - ????
Side effects
Nano formulated NSAIDS

• Nanoparticle drug delivery systems are engineered technologies that

use nanoparticles for the targeted delivery and controlled release of
therapeutic agents.

• The modern form of a drug delivery system should minimize side-effects

and reduce both dosage and dosage frequency.

• What are these ??

 Nano – basis ?

• These are low dose micro-ionised NSAIDs. Advanced scientific technology is used to
produce submicron sized drug particles which are 10–20 times smaller than their
original size.

• The theory is that an increased drug surface area will enhance dissolution and
absorption of the drug with the aim of achieving similar effects to normal NSAIDs
with reduced adverse effects

• Currently approved nano formulations by the FDA in the US are indomethacin

(tivorbex) and diclofenac (zorvolex) for the treatment of mild to moderate pain
AVAILABLE IN INDIA !
Hydrogen sulphide releasing drugs (H2S)
• Hydrogen sulphide is said to have vasodilatory properties and anti-
inflammatory properties.
• It has an important role in gastrointestinal mucosal homeostasis.
• Early animal studies have shown lower GI and CV toxicity when this
compound was used with diclofenac and naproxen than when these
drugs were used alone.
• Drugs containing this compound are still in the preclinical stage of
development.
Combine NSAIDs and H2S – make release
H2S
CINODS/NONSAIDs
• Cyclooxygenase-inhibiting nitric oxide (NO) donors
(CINODS/NONSAIDs) are a new class of drug in development.
• They target multiple pathways with one drug.
• NO is a potent vasodilator and has protective effects on the GI tract.
• It protects the integrity of the gut by stimulating release of
bicarbonate and mucus, protects epithelial cells from injury and
inhibits the release of inflammatory mediators.
• By adding NO to NSAIDs it is hoped that the adverse GI effects will be
reduced.
• Nitric Oxide and ibuprofen

• Nitric Oxide and flurbiprofen

 COX LOX inhibitors
• Licofelone is both an analgesic and an anti-inflammatory. Inhibition of 5-
lipoxygenase (5-LOX) may reduce the gastrointestinal toxicity associated
with other nonsteroidal anti-inflammatory drugs (NSAID), which only
inhibit cyclooxygenase (COX).
• Licofelone is the first drug to inhibit both.

• 2 – 5 mg / kg

• Decreased allodynia and hyperalgesia – more in animal studies

• Stomach safe
Oliceridine – new opioid
• Oliceridine is effective in the management of moderate to severe pain
and appears to be associated with lower risk of nausea and vomiting

1 mg/ ml
Maximum of 3 mg IV

Onset is within 2 – 5
minutes
TECHNOLOGY
• Better pain relief

• Less opioids
Liposomal bupivacaine
 Structure
• Liposomes are microscopic structures consisting of a phospholipid bilayer
encapsulating an aqueous core.
• They may be unilamellar, multilamellar, or multivesicular.
• Unilamellar liposomes consist of a single lipid bilayer surrounding the
aqueous core, whereas multilamellar liposomes consist of concentric lipid
layers.
• Multivesicular liposomes (MVL), however, consist of nonconcentric lipid
bilayers.
• The nonconcentric nature of MVL confers characteristic drug release
patterns from the aqueous core that are different from the unilamellar and
multilamellar liposomes, leading to increased stability and longer duration
• Liposomal bupivacaine has been FDA approved for single dose wound
infiltration in postoperative pain relief among patients undergoing
hemorrhoidectomy and bunionectomy.
When injected what happens !
• The sole fraction of bupivacaine available to enter the CNS and the
cardiovascular system is the free (ie. non-liposomal) formulation,
because multilamellar liposomes do not cross the blood-brain barrier.
• Liposomal bupivacaine is released into the plasma in two different
ways after local tissue infiltration. Initially, plain bupivacaine in the
“liposomal bupivacaine” solution is systemically absorbed.
• Subsequently, there is a gradual, sustained release of bupivacaine
from multilamellar vesicles.
• This may explain why despite a large amount of drug deposition, less
systemic toxicity is seen.
Cost ?
• 600 mg – upto 3 days
• Better than placebo but ?with bupivacaine ?

• RFA – later the injection

• Trigger point injections
• Migraine nerve blocks

• Outpatient pain management

• Toxicity profile similar

• Less blood levels after injection than bupivacaine

• Epidural and block use – still ??

• There are a few drugs which are
not actually recent but

• Not much used nowadays

Tapentadol
• Tapentadol is a novel, centrally acting analgesic with dual mechanism
of action, combining mu-opioid receptor agonism with noradrenaline
reuptake inhibition in the same molecule.
• It has an improved side effect profile when compared to opioids and
nonsteroidal anti-inflammatory drugs.
• The dual mechanism of action makes Tapentadol a useful analgesic to
treat acute, chronic, and neuropathic pain.
• Tapentadol is available as 50, 75, and 100 mg oral tablets.
• ER preparation is studied
• Injections are just on the anvil
Flupirtine 100 mg tablets
• Flupirtine is neither an opioid nor a non steroidal anti-inflammatory
drug (NSAID) producing its analgesic action through blockade of
glutamate N-methyl-D-aspartate receptor.
• It is devoid of adverse effects of routinely used analgesic drugs, but is
equally efficacious in reducing pain sensation.
• It has a distinctive mechanism of action, exerting a dual therapeutic
effect with both analgesic and muscle relaxant properties that has
utility in the treatment of pain, including that associated with muscle
tension.
Advantages
• Empty stomach also possible
• Long-term use of opioids for treatment of pain leads to constipation,
nausea, sedation, confusion, pruritis, urinary retention, tolerance, and
dependence.
• These adverse effects were not seen with flupirtine when given daily
for 12 months in chronic pain

• What I usually get is less efficiency and mild sedation

Summary
• Why do we need new
• COX 1 and 2
• Newer drugs – parecoxib, celecoxibs, lornoxicam, meloxicam etc
Newer technologies – Nano, NO and H2S
LIGNO PATCH ,
Other drugs
Liposomal bupivacaine
We need to make advances to remain static

• LONG LIVE THE ISA

• THANK YOU ALL