Pain Treatment: Nociception and Co-analgesics

Some Clinical Elements of Pain Treatment

• Nociception is a complex process.

Nociception Process

• Transduction occurs.
• Conduction occurs.
• Modulation occurs.
• Perception occurs in the cortex.

Pain Treatment

• Opioids, NSAIDs, and co-analgesics can be used to treat pain in the brain.
• Local anesthetics, opioids, and co-analgesics can be used to treat pain in the spinal cord.
• Local anesthetics and co-analgesics can be used to treat pain in the peripheral nerves.
• Local anesthetics, opioids, NSAIDs, and co-analgesics can be used to treat pain in peripheral organs.

Co-analgesics

• Antiepileptics like Topiramate, Gabapentin, and Pregabalin are often used.
• Agonists of α2 rec (clonidine).
• Indirect agonists of M rec (neostygmine).
• Antagonists of NMDA (ketamine, dextrometorphan, amantadine).
• Mg++.
• TCAs like Doksepine and Amitryptyline.
• Cytokine inhibitors (pentoksyfilin).

Balanced Analgesia

• Analgesia should be balanced with pain.

Hospital Stay Assessment

• Blood pressure (BP).
• Heart rate (HR).
• Respiration.
• Temperature.
• Diuresis.
• Pain score.

Pain Treatment

• Polytherapy with drugs that have different mechanisms of action helps prevent combining drugs with the same mechanism of action.
• Consider the side effects and toxicity of used drugs.
• Consider all drugs interactions.
• Avoid dose escalation over recommended doses.
• Use co-analgesics.
• Treat the cause of the pain.
• Introduce alternative analgesic methods like psychotherapy.
• Consider psychosomatic symptoms.
• Central acting cholinolytics "opens" Central nervous system (CSN) for pain stimuli

Drug Interactions

• Induction of liver metabolism: Barbiturates, RMF, Alcohol.
• Inhibition of liver metabolism: Ketoconazole, Omeprazole.
• Changing of metabolism: Paracetamol/Alcohol
• Increased elimination: Furosemide, Vitamin C.
• Delayed absorption: Food.
• Decreased absorption: Antacids, Prokinetic.
• Potentiation of action of oral hypoglycemic and anticoagulant drugs: NSAIDs.
• Depression of CSN: Opioids, Sedatives, Hypnotic, Alcohol.
• Diminishing of analgesics effectiveness: Cholinolytics.
• Increased toxicity: Renal insufficiency, Hypoalbuminemia, Dehydration.

WHO Analgesic Ladder for Cancer Pain

• Step 1: Non-opioid ± Adjuvant for pain.
• Step 2: Weak opioid + Non-opioid ± Adjuvant for pain persisting or increasing.
• Step 3: Strong opioid ± Non-opioid ± Adjuvant for freedom from cancer pain.

Non-Opioid Analgesics

• Acetylsalicylic acid and NSAIDs.
• Paracetamol Methamizol.
• Nefopam.
• Flupirtyne.

Opioids

• Weak opioids: Tramadol, Buprenorphine, Codeine, Nalbufine.
• Strong opioids: MF, FNT and derivatives, Oxycodone.

Other Analgesics and Treatments

• Local anesthetics (LA).
• Triptans.
• Ziconotide.
• Cannabinoids.

Co-Analgesics

• Topiramate.
• Gabapentine.
• Pregabaline.
• Valproate.
• TCA.
• Mexyletine.
• GCS.
• Clonidine.
• NMDA Antagonists.
• Duloxetine.

Analgesics Developed Between 1960-2009

• 59 drugs identified as analgesics have been introduced and remain in use.
• 39 drugs were specifically developed as analgesics.
• 20 drugs were developed for non-pain indications, but their effectiveness in pain was later confirmed by a meta-analysis or by an FDA.

Drugs with a Modified Molecular Target

• Pentazocine, Sumatriptan, and Celecoxib fit the category due to a novel selective mechanism.

Drugs Acting on Novel Molecular Targets

• 4 drugs have completely novel molecular targets.
• Only Sumatriptan was sufficiently effective to motivate the introduction of similar drugs acting at the same target (triptans).

Tapentadol

• Tapentadol is a tramadol derivative.
• It is a strong opioid that affects mi receptors.
• Tapentadol inhibits the reuptake of NA but not 5HT, leading to a weaker proemetic effect.

Nefopam

• Analgesic that does not possess anti-inflammatory or antipyretic effects.
• It has moderate and quick action.
• Used for moderate and strong pain.
• Can cause visual disturbances, apathy, hallucinations (older people), and drying of mucosa.
• Functions by monoamine reuptake inhibition, activation of inhibitory pathways in the spinal cord, NMDA inhibition (questionable), and Na-ch inhibition.

Flupirtine

• A triaminopyridine derivative with central analgesic action.
• It doesn't affect opioid receptors and has no tolerance or dependency issues.
• Effective with weak and moderate pain, especially if combined with increased muscle tonus.
• Removed from the market in 2018 due to liver toxicity.
• Opens K+-ch from inside (Selective Neuronal Potassium Channel Opener - SNEPO).
• Causes antagonism on NMDA rec and NMDA blocked by Mg2+ so Ca2+ infflux inhibited.

Targine

• Targine: Oxycodone + naloxone used for visceral pain.

New Directions in Pain Management:

• NCX – NO-ASA: Nitrophenack – NO-Diclophenac and Naproxcynod – NO-Naproxen
• DexIbuprofen (purified S(+)).
• DexKetoprofen – Dexac – 50 mg (Ketoprofen – 100 mg).
• Arthrotec – Diclofenak+Mizoprostol.
• NSA+Omeprazol (Dicloduo) and ASA+Omeprazol.
• NABUMETON, a prodrug metabolized to a strong inhibitor of COX-2.
• Antagonists of CGRP and Agonists of TRPV1

Effectivity of postopertive analgesia

• 38 to 46%
• One day surgery - 82%

Strong Analgesia

• Can lead to no pain but can cause N/V, urine retention or puritis
• Can lead to Respiratory Depression

Trauma Effects

• Trauma can cause Metabolic and endocrine changes, SNS stimulation, and Neuroplastic changes.
• Neuroplastic changes can be the case of fascilitation of pain transmission, peripherial hypersensitivity (in wound) and Increase in muscle defence.
• Trauma can cause behavioural changes or fear
• Fear can lead to insomnia, helplesness, depression, pneumonia, Heary hypoxia or Angina Pectoris
• Immobility can cause lung issues or thrompophlebitis

Post Abdomen Surgery Treatment

• Day 1 of treatment may include Ketoprofen 2 x 100 mg and paracetamol 4x1,0 both intravenously.

Post Abdomen Surgery Treatment: unstable Hypertonia

• Day 1 of treatment may include ketoprofen 2 x 100 mg, paracetamole 4x1,0, MF 6x5 mg an methamisole 4x1,0 all intravenously.

Post Abdomen Surgery Treatment: Haemophilia A

• Day 1 of treatment may include Ketoprofen 2 x 100 mg, paracetamole 4x1,0 and MF 6x5 mg and Nefopam 3x60mg all intravenously

Post Abdomen Surgery: Advanced Asthma or Nasal Polyps

• Day 1 of treatment may include Paracetamole 4x1,0, Tramal 4x50 mg I.V.

Post Abdomen Surgery Therapy: Spinal Probles

• Day 1 of treatment may include Ketoprofen 2 x 100 mg and paracetamol 4x1,0 , MF 6x5 all intravenously plus Baklofen 3x5 mg po

Pregnancy

• When patient is pregnant is important to asses is is save to treat ot not.

Pregnancy Classifiation - Drugs

• Class A drugs: Generally considered safe; Controlled studies show no risk in 1st trimester; no evidence of 2nd or 3rd trimester risk; risk of fetal harm remote
• B CLASS [Caution advised] Animal studies show no risk or adverse fetal effects but controlled human 1st trimester studies not available/do not confirm; no evidence of 2nd or 3rd trimester risk; fetal harm possible but unlikely.
• C CLASS Animal studies show adverse fetal effect(s) but no controlled human studies OR no animal or human studies; weigh possible fetal risk vs. maternal benefit
• C/D/D CLASS Category C in 1st trimester but positive evidence of human fetal risk in 2nd and 3rd trimester; maternal benefit may outweigh fetal risk in serious or life-threatening situations.
• D CLASS: Weighing risk/benefit: Positive/evidence of human fetal risk maternal benefit may outweigh fetal risk in serious/life threatening situations.
• X CLASS: Contraindicated/positive evidence of serious abnormalities in animals or humans; fetal risk clearly outweigh material benefit.

Pregnancy risk category - FDA

• Articaine C class drug whose lactation effect is not known
• Bupivacaine C class lactation effect is S?
• Lidocaine B class lactation effect is S
• Mepivacaine C classs lactation effect is S?
• Prilocaine B classs lactation effect is not known
• Epinephrine C class, *NS lactation effects and is only safe to use in small doses

Systemic Toxicity

• Pregnant are at a higher risk after Bupivacine

Max Doses of LA

• How much of LA patient has is important if we consider their body weight and age, lets say 88Kg and 32 Yo men
• Lidocaine amp. 2% - 2 ml/ 1:100 000, Articaine amp. 4% - 1.8 ml/ 1:200 000
• Max dose = 7 mg/kg (3mg/kg without A !!!)

Using Lidocaine 2 %: Maximal Doses of LA

• Max dose = 7 mg/kg
• 7mg/kg x 88kg=616 mg
• 40 mg/2mL
• 616mg/40 mg=15.5 amp

Using Articaine 4 %: Maximal Doses of LA

• Max dose 7 mg/kg
• 7mg/kg x 88 kg= 616 mg
• 72 mg/1.8mL
• 616 mg/72 mg = 9 amp
• If you want to count the amount in mg: ml x concentration (%) x 10 = mg

Maximimum doses of Epinephrine

• CVS patient 40 ug
• healthy patient 100-200 ug

Breast Feeding

• Drug penetration to the milk should be block, pull away or think.

Breast feeding - Drug Penetration

• Penetration to the milk- consider -small, -lipofilic, -weak bases or -weakly bounded with alb drugs.

Drugs and lactation

• Category I drugs are safe because for nursing infant; medication usually compatible with breast-feeding, no penetration to milk
• Category II drugs have safe penetration to the milk
• III A and IIIB have Penetration to milk propably safe of Penetration to milk possibly not safe
• IV is not safe

Drug in breastfeeding

• RID -ratio infant dose: dose absorbed by child/dose taken by mother
• RID = ID/MD x 100%

RID Values

• RID = < 10% safe
• RID of over 90% of drugs is < 10%
• webside - laktacyjny leksykon leków

Breast feeding considerations where women have absces

• General anesthetic
• Epidural/SAA? LA + SA
• LA
• Oral analgetics
• Polish Mother - consider any analgesia

Breast feeding

• Good medical knowledge is good to know plasma half life of drugs and LA or Sedatives.
• Most drugs will penetrate to the milk but will be safe for child after.
• 6x T1/2
• (1.5%)

Blood Plasma Half Life

• 90 min for Lidocaine, Mepivacaine, Prilocaine where you can give milk after 540 min
• Midazolam - ~2.0 hr. where you can give milk after 12 hrs
• 27 min in Articaine which will allow you to give milk after 162 min

Analgetics in lactating mothers

• Short plasma Articaine HCI T1/2 of (27 min vs 90 min) ,is preffered.
• Propofol is safe because its has short and quick action, no active metabilities, poor oral abs. but it has Insignificant level in milk after 2h (2.5 mg/kg).
• Midazolam is great because of he short and quick action, RID – 0.6%, some oral abs. and is Safe after single dose (1-5 mg)

Opioids in lactating mothers:

• Most of them are low amount so there are save
• Morfine is preffered.
• Fentanyl and derivatives seems to be safe in small doses.
• Nalbufine RID - < 1%
• Be careful about norpetidine (Dolargan) and Oxycodone because they cause respiratory depression
• Codeine is contraindicated

NSA in lactating mothers:

• Seems to be safe with exeption of ASA (Rey's S)
• Salicylanes - RID 10%
• Methamizole – RID – 6.8%
• Paracetamol/Ibuprofen safe

Pain Delivery options

• Epidural analgesia using Bupivacaine/Ropivacaine+ opioid which can cause Hipotention,Longer delivery, instrumental delivery or Motor blockade
• CSE
• Regional anestesia in pericervicalis or sacral area

What analgesia is allowed

• TENS
• Inhaled N2O - Entonox (N2O), Isonox (N2O+Izofluran) - risc of hyperventilation
• Opioids and Schould be limitated/avoided exept FNT/ Diamorphine and PCA or Remifentanyl

Threament of Neuropathic Pain

• Symptomatic threatment using TCA, alpha 2 agonists, antiepileptic drugs, LA plasters or QUTENCA – (capsaicine 8% !) – agonist of vaniloidin -rec. TRPV-1 (30 min- effect 3 mth)
• Opioids (periodically)
• Non pharmacologic threatment

Efficacy of Pain Management

• Pharmacotherapy effective in about 80-85% patients
• Standard therapy is ineffective must be treated in specialized pain treatment clinic such as neuronal blockades, neurolysis, accupuncture, rehabilitation or other specialists.