Pain Management 2

Principles of Pharmacological Treatment

• Treatment should follow the WHO pain ladder.
• Taking a careful drug history is critical.
• Know the pharmacology of the prescription.
• Regimens should start low and progress slowly.
• Regimens should be reviewed regularly.
• Remember drugs can cause illness.

Aims of Pain Treatment

• Increase sleep period
• Achieve no pain at rest
• Achieve less/no pain during physical activities

Systemic Pharmacological Treatments

• Treatments are divided into Opioids, Non-Opioids and Adjuvants

Classification of Nonselective COX Inhibitors (Traditional NSAIDs)

• Salicylates: Aspirin
• Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
• Anthranilic acid derivative: Mephenamic acid
• Aryl-acetic acid derivatives: Diclofenac, Aceclofenac
• Oxicam derivatives: Piroxicam, Tenoxicam
• Pyrrolo-pyrrole derivative: Ketorolac
• Indole derivative: Indomethacin
• Pyrazolone derivative: phenylbutazone, Oxyphenbutazone

Preferential COX-2 inhibitors

• Nimesulide, Meloxicam, Nabumeton.

Selective COX-2 inhibitors

• Celecoxib, Etoricoxib, Parecoxib.

Analgesic-antipyratics with poor antiinflammatory action

• Para aminophenol derivatives: Paracetamol
• Pyrazolone derivative: Metamizol, Propiphenazone
• Benzoxazocine derivative: Nefopam

Non-Opioid Analgesics

• Possess analgesic, antipyretic, and anti-inflammatory actions.
• Some act as an analgesic and antipyretic only, such as metamizol and paracetamol.
• For mild and moderate pain.
• There is no tolerance or addiction associated wth use.

Commonly Used Pharmacological Methods

• Paracetamol
• NSAIDs: Aspirin, Ibuprofen, Ketorolac, Diclofenac, Aciclofenac
• Opioids: Codeine, Tramadol, Morphine, Fentanyl
• Antispasmodic: Hyoscine Butylbromide
• Adjuvants: Antidepressants and anticonvulsants, Topical analgesics, Muscle relaxants, Antianxiety medications
• Regional Anaesthesia

Salicylates: Aspirin

• Possess analgesic, antipyretic, and anti-inflammatory actions.
• Aspirin (Acetylsalicylic acid) converts to salicylic acid in the body, which is responsible for its action.
• Aspirin irreversibly inactivates COX-1 and COX-2.
• This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2.

Paracetamol

• Inhibits prostaglandin synthesis in the central nervous system.
• Doses range from 500mg to 1g every 4-6 hours, with a maximum of 2.5-4g per 24 hours.
• Can be administered orally or intravenously.
• Effective as both an analgesic and antipyretic.
• Used for mild pain (Pain score 1-3).
• Risk of hepatotoxicity.
• Contraindications include heavy alcohol use, acute/chronic hepatitis.
• Acetaminophen (paracetamol) is not an anti-inflammatory drug.
• It is a poor peripheral inhibitor of the enzyme cyclooxygenase.
• Acetaminophen does not affect platelet function.
• Useful as a first-line agent to relieve headache, muscle pains, and general pain.
• Lacks significant anti-inflammatory properties.
• Should not be used for inflammatory processes such as rheumatoid arthritis.
• Useful when nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in patients with a history of gastrointestinal or renal problems.

NSAIDs

• Commonly prescribed analgesics.
• Act by inhibiting COX-1 and COX-2 enzymes.
• Results in a decreased production of prostaglandins from arachidonic acid.
• Are Analgesic, antipyretic, and anti-inflammatory.
• Effective for bone and inflammatory pain.
• Administered via oral, topical, or intramuscular route, IV available for Ketorolac.
• They function by blocking inflammation at the site of pathology, altering pain perception in the central nervous system (CNS).
• Peripherally, cyclooxygenase is an enzyme that converts arachidonic acid to a number of prostaglandins.
• Inflammatory prostaglandins sensitize nerve endings to the action of bradykinin, histamine and other inflammatory factors.
• Centrally, NSAIDs work by directly acting on the CNS and altering spinal nociceptive processing.
• Exact mechanism of action of NSAIDs in the CNS is not known.
• Peripherally, NSAIDs block the action of cyclooxygenase and halt the conversion of arachidonic acid into inflammatory prostaglandins. The block is the key step in the inflammatory cascade.
• The cyclooxygenase enzyme has two isoforms: COX-1 and COX-2.
• COX-1 isoform catalyzes the production of prostaglandins that helps regulate normal physiologic function.
• COX-2 isoform facilitates the production of inflammatory prostaglandins. Most NSAIDs block both the COX-1 and COX-2 isoforms of cyclooxygenase.
• Non Specific NSAIDS produces bleeding tendency and peptiuc ulcer.

NSAIDs adverse effects

• Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding
• Central nervous system: Headaches, tinnitus, and dizziness
• Cardiovascular: Fluid retention hypertension, edema, and rarely, congestive heart failure
• Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia
• Hepatic: Abnormal liver function tests and rare liver failure
• Pulmonary: Asthma
• Rashes: All types, pruritus
• Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria

NSAIDs Contraindications

• Peptic ulcer
• Chronic liver disease
• Diabetics
• Pregnancy
• Breastfeeding mothers
• Sensitive to it

Hyoscine Butylbromide

• Used to treat spasmodic and crampy abdominal pain.
• Also treat renal colic and bladder spasms
• Route: oral, IV or IM.
• Dose: 20mg IV.
• Side Effects: sleepiness, vision changes, allergies, triggering of glaucoma.

Opioids

• Generic term for natural or synthetic substances that bind to specific opioid receptors in the CNS, producing an agonist action and are also called narcotics.
• They act as a chemical substance has a morphine-like action in the body.
• They activate receptors that modulate perception of painful stimuli (nocioceptive pain).
• They act within the brain and spinal cord to alter nociceptive transmission.
• There are three opioid receptors (Mu, kappa, delta).
• Activating opioid receptors in midbrain turns on descending inhibitory system
• Activating opioid receptors on the second order pain transmission cells prevents ascending transmission of pain signals
• Activating opioid receptors at the central terminals of C fibers in the spinal cord.
• Activating opioid receptors in the periphery inhibits activation of nociceptor and inhibits the cells that may release enflamatuary mediators

Most of available opioid analgesics

• Act at Mu-opioid receptor
• Activation of Mu-opioid receptor causes analgesia, euphoria, respiratory depress, nausea, vomiting, decreased gastrointestinal motility, tolerance, dependence
• -, -opioid receptor has analgesia
• dyshoria, Psychotomimetic
• Affective behaviour, proconvulsant ()
• Not cause respiratory depression or to decrease GI motility
• → Analgesia without -opioid side effect
• Morphine receptor activation
• Fentanyl, sufentanyl are more selective receptor agonist

Opioid actions

• By closing voltage gated ca channels on presynaptic neuronal terminals, reduce neurotransmitter release.
• Inhibits postsynaptic neurons by increasing K channel conductance.
• Interact with adenylate cyclase system

Opioids - Agonist Binding

• Results in inhibition of adenylyl cyclase activity.
• Stimulates K+ current.
• Inhibits voltage-gated Ca2+ channels.
• Results in decreased release of neurotransmitter (substance-P, neurokinin A, neurokinin B, glutamate).
• The naturally occurring alkaloid, morphine, is the prototype drug.
• Decrease N.E , substance p in CNS synapses
• Decreases pain perception and increases pain threshold
• Used for moderate to severe pain
• Available to administer via various routes
• Short acting opioids for acute pain

Classification of Opioids

• Natural opium alkaloids:
  • Morphine
  • Codeine
• Semisynthetic opiates:
  • Diacetylmorphine (Heroin)
  • Pholcodeine
• Synthetic opioids:
  • Pethidine (Meperidine)
  • Fentanyl, Alfentanil, Sufentanil, Remifentanil
  • Methadone
  • Dextropropoxyphene
  • Tramadol

Route of Administration for Opioids

• Almost any route can be used
• The oral or transdermal route is preferred for long-term use. (both are effective and provide stable blood levels)
• Oral
• Transdermal forms
• Effervescent tablets
• IM route
• The IV route
• Continuous IV infusion

Effects of Morphine

• Analgesia: Affects both sensory and emotional components of pain. Reduces the pain experience, especially the affective aspect.
• Euphoria: Can cause a pleasant floating sensation with lessened anxiety in intravenous drug users.
• Sedation: Clouding of mentation, little/no amnesia, no motor incoordination. Induces sleep in the elderly, but they can be easily aroused.
• Respiratory Depression: Inhibits brainstem respiratory mechanisms. May not be tolerated in individuals with increased intracranial pressure, asthma, or chronic obstructive pulmonary disease
• Cough Suppression: Codeine is particularly effective. May allow accumulation of secretions and lead to airway obstruction and atelectasis.
• Temperature Regulating Centre Depression: can increases chances of hypothermia
• Vasomotor Centre Depression: Causes a fall in BP
• Morphine stimulates CTZ (nausea, vomiting)
• Edinger Westphal nucleus of III nerve is stimulated (miosis)
• Vagal center bradycardia
• Miosis: Constriction of the pupils happens when simulating Edinger Westphal nucleus by III nerve and is a valuable pharmacologic action to which little or no tolerance develops in the diagnosis of opioid overdose.

Truncal Rigidity

• Reduces thoracic compliance and thus interferes with ventilation.
• Can be overcome by administration of an opioid antagonist, which will also antagonize the analgesic action of the opioid.
• Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.

Peripheral Effects - Cardiovascular System

• Bradycardia
  • Meperidine is an exception (can result in tachycardia)
• Hypotension - due to:
  • peripheral arterial and venous dilation
  • depression of vasomotor centre
  • release of histamine.
• Increased PCO₂ leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.
• Opioid receptors exist in high density in the gastrointestinal tract.
• Constipating effects of the opioids are mediated through an action on the enteric nervous system as well as the CNS

Gastrointestinal Tract affects

• No tolerance.
• Constipation
• Gastric secretion of hydrochloric acid is decreased
• Propulsive peristaltic waves are diminished leading to the tone increased
• Delays the passage of the fecal mass and allows increased absorption of water, which leads to constipation
• So used in the management of diarrhea
• Sphincter of Oddi may constrict contracting biliary smooth muscle, resulting in biliary colic
• Renal function is depressed by opioids.
• Decreased renal plasma flow.
• Enhanced renal tubular sodium reabsorption. Ureteral and bladder tone are increased, which means
• Renal increased sphincter tone may precipitate urinary retention
• Ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone.

Uterus

• May prolong labor
• Peripheral and central actions of the opioids can reduce uterine tone

Neuroendocrine

• Stimulate the release of ADH, prolactin, and somatotropin
• Inhibit the release of luteinizing hormone
• CNS effects and peripheral histamine release may be responsible for these reactions
• Pruritus and occasionally urticaria occur when administered parenterally.

Miscellaneous effects of Opioids

• The opioids modulate the immune system causing:
  • Lymphocyte proliferation.
  • Antibody production.
  • Chemotaxis.

Clinical Uses of Opioid Analgesics

• Analgesia
• Cough
• Diarrhea
• Acute Pulmonary Edema
• Balanced anaesthesia
• Preanaesthetic medication
• Relief of anxiety and apprehension

Toxicity & Undesired Effects of Opioids

• 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)

Tolerance and Dependence

• With frequently repeated therapeutic doses of morphine, there is a gradual loss in effectiveness
• To reproduce the original response, a larger dose must be administered
• Along with tolerance, physical dependence develops
• Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered.
• Reduced effectiveness to a given dose over time (Tolerance).
• suspect opioid tolerance if dose is increasing.
• disease progression can reduce effectiveness
• psychological distress and spiritual pain can reduce effectiveness'

Addiction

• Acceleration of abuse patterns onto a primary illness.
• Characteristics can includes -Psychological dependence -Compulsive use -Loss of control over amount and frequency of use -Loss of interest in pleasurable activities -Continued use of drugs in spite of harm

Pseudoaddiction

• Drug-seeking behavior linked to a person's need to relieve pain and suffering rather than an obsession with the mood-altering effects of medication.

Adjuvant drugs

• These are not strictly pain medications.
• They may relieve discomfort, potentiate the effect of pain medications, and reduce the side effect burden
• Includes Antidepressants and anticonvulsants, Topical analgesics, Muscle relaxants, Corticosteroids

Antidepressants and Anticonvulsants

• Anticonvulsants:
  • Carbamazepine 200-400 mg bid Monitor WBCs when starting treatment
  • Gabapentin 300 mg bid-1200 mg tid Preferred drug in this class
  • Phenytoin 300 mg once/day Limited data; 2nd-line drug
  • Pregabalin 75-300 mg bid Mechanism similar to gabapentinS but more stable pharmacokinetics
  • Valproate 250-500 mg bid Limited data
• Antidepressants:
  • Amitriptyline 10-25 mg at bedtime May increase dose to 75–150 mg over 1-2 wk, particularly if significant depression is present may not need high doses not recommended for the elderly
  • Desipramine 10-25 mg at bedtime Better tolerated than amitriptyline May increase dose to 150 mg or sometimes higher
  • Duloxetine 30 mg bid Better tolerated than tricyclic antidepressants

Topical analgesics

• Including Local anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), the neurolytic substance capsaicin.
• These topical medications provide localized relief, targeting tissue on which they are directly applied.
• Local anesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane.
• Capsaicin is thought to lead to the depletion of substance P in C fibers, where C fibers are unmyelinated nerves that transmit pain.
• Topicals can be employed for pain in a focal area when there is poor compliance with oral medication and the patient has adverse effects with oral medication. They are used when patients are completely adverse to taking pills.
• Topical medications can be used with an oral medication or as a stand-alone pain medication.

Muscle Relaxants

• Defined by the drug which affects skeletal muscle function and decreases the muscle tone.
• It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia.
• Practitioners use muscle relaxants as first-line agents to reduce spasticity in upper motor neuron syndromes.
• It is helpful with conditions such as multiple sclerosis, spinal cord injury, cerebral palsy, and poststroke syndrome.
• Muscle also helps for acute muscular pain or spasms from peripheral musculoskeletal conditions.
• Act peripherally at the muscle itself as well as act in the central nervous system (CNS).
• Three of the most commonly used centrally acting muscle relaxants are Baclofen Zanaflex and Flexeril.
• Flexeril has an unknown mechanism of action, however, experts believe that the muscle relaxant works at the level of the brainstem, decreasing the firing of motor neurons.
• All muscle relaxants can cause ;
• dizziness, drowsiness, dry mouth, and weakness.
• Baclofen acts like the inhibitory neurotransmitter -aminobutyric acid (GABA).
• It decreases activity from central neural outputs, primarily in the spinal cord, that control the contraction of skeletal muscle. and has analgesic effects
• Zanaflex works as an agonist of the noradrenergic receptor. and decreases neurotransmitters. By stimulating the receptor this increases.
• Corticosteroids reduce the mucus secretion by inhibiting the release of secretagogue from macrophages.
• Corticosteroids enhance the beta-adrenergic response to relieve the muscle spasm.
• They have an inflammatory effector function.

WHO Three-Step Analgesic Ladder

• The first step is Non-opioid + Adjuvant for lower level pain - pain persists or is increasing if the first step does not work
• The second step is increases the pain to Opioid for mild to moderate pain Non-opioid + Adjuvant - If that step is still inefficient ( pain persists or is increasing) step 3 is initiated
• The third steps is for extreme pain is Opioid for moderate to severe pain+ Non-opioid+ Adjuvant

Quality of Life Step

• The goal in treating pain is pain control and maintenance is achieved
• It is also important to note that each step the dose is pain persisting/increasing

Treatment

• Treatment depends on the type and intensity of the pain
• Aetiological
• Symptomatic

WHO 3 step approach to pain meds

• Patients 1-3 can be Non opioid, adjuvant Patients 4-7 can be Opioid for mild to moderate pain + adjuvant
• Patients pain level is and increased pain.
• Patients 8-10 can be Opioid for moderate to severe pain + adjuvant
• Non-opioid analgesics include paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs).
• Weak opioid analgesics include codeine and tramadol - Should be combined with with on or one more
• Strong opioid analgesics include foremost morphine and the combination of steps 2 to 1 is recommended

NOCICEPTION AND DRUGS

• Transduction: Occurs with Noxious stimulus and is translated into electrical activity at sensory nerve endings
• Medications used include COX-2 inhibitors, local anesthetics, NSAIDs
• Transmission: Occurs by propagating action potential through with the spinothalamic pathway
• Medications used include local anesthetics
• Modulation: Dampening or amplifying of pain signal along the pathway
• Medications used include clonidine dexmedetomidine opioids
• Perception: Can cause subjective sensation of pain
• Medications used include acetaminophen with alpha-2

Common Initial Drug treatment

• Headache Paracetamol NSAIDs
• Migraine :paracetamol NSAIDs
• Menstrual crampsNSAIDS
• Minor trauma such as a bruise abrasionsprain :paracetamol NSAIDs
• Severe trauma burnsbone fracture or severe NPrain Opioids
• Strain or pulled muscle-NSAIDs muscle relaxants
• Minor pain after surgery paracetamol NSAIDs Severe pain after surgery - Opioids Muscle Aches -paracetamol NSAIDs Toothache or pain from dental procedures paracetamol NSAIDs Kidney stone pain - paracetamol NSAIDs opioids
• Pain due to heartburn or gastroesophageal reflux disease -antacid H2 antagonist proton-pump inhibitor
• Chronic back pain- paracetamol NSAIDs
• Osteoarthritis pain:-paracetamol NSAIDs

Step 1 Analgesic treatment

• Non-opioid analgesics, (COX-2, Aspirin, Acetaminophen, Diclofenac, Ibuprofen, Tenoxicam,
• PanadeineNurofenPain rating 1-2-3)

Step 2 Analgesic treatment

• Mild opioid is added not step 1 (Codeine, Propoxyphene, Tramadol, Sevredol, DHC Continus, Dihydrocodeine tartate Pain rating 4-5-6)

Step 3 Analgesic treatment

• Opioid for moderate to severe pain is used and titrated to effect
• (OxycodoneMorphineFentanylPethidineKetamine Pain rating 7-10)

In providing postoperative pain relief

• Opioids, Alphaagonists assist in spinal cord tracts.
• Local anesthetics, aiding and alpha agonists are assisting that dorsal horn
• And Local anaesthetics used Anti-inflammatory Drugs for peripheral nerves which are going into the peripheral nociceptors
• In determining the level of pain medication for pregnancy there is a set level of medication pain medication to treatment if it's possible to do so medication should be determined for which type of area it's in for safety.