Treatment of pain 1.2 Flashcards
Mixed agonist antagonists
- Pentazocine
- Buprenorphine
- Tramadol
Pentazocine (Talwin)
• Oral administration
• Weak µ-antagonist; κ agonist
• Analgesia, sedation, respiratory depression
• May block morphine mediated analgesia
• May precipitate withdrawal in patients receiving opioids
• Used primarily for acute pain treatment
• Naloxone now included in Talwin to prevent drug abuse
• agonists produce psychotomimetic effects
• mixed agonists/antagonists, in general, have a lower
potential for abuse
• Tripelennamine, an antihistamine, given i.v. to patients
receiving pentazocine experienced higher degrees of
euphoria
Buprenorphine (Buprenex)
• Partial agonist at µ receptors; antagonist at κ
receptors
• Less effective analgesic than morphine
• Route of administration: i.m./i.v./ sublingual
• Recently approved by FDA for treatment of
opioid dependence; given sublingually for this
effect ± naloxone
• Used here for pregnant addicts (see Chaffin
lecture)
Tramadol (Ultram)
• Chemically unrelated to opiates • Binds opiate receptors • Inhibits NE and 5-HT reuptake • Partial inhibition by naloxone • Side effects – constipation, nausea, vomiting, dizziness, drowsiness • Oral administration for moderate pain
Opiate antagonists
• Bind with highest affinity to µ receptor; no analgesic effects
• Used to treat opioid poisoning; prevention of
dependence/addiction
• Naloxone (Narcan):
• i.m./i.v. t1/2 ∼ 1 h
• Nalmefene (Revex):
• i.v., t1/2 ∼ 10 h, more potent than naloxone
• Naltrexone (Revia, Trexan, vivitrol):
• effective orally t1/2 ∼ 24 h; approved for adjunct treatment in
alcoholism and opioid treatment
• IM (vivitrol) once every 4 weeks injection (slow release depot
formulation)
• In opioid-dependent subjects, antagonists can induce withdrawal
Non-Analgesic Use (antitussive)
• Dextromethorphan (Delsym, Tussin): • synthetic derivative of morphine • suppresses response of cough center; elevates threshold • no analgesia • less constipation than codeine • not antagonized by naloxone • Robotripping, major agent in cough syrup abuse in teens
Alpha 2 adrenergic agonists:
Clonidine
Mechanism of
Action: NE inhibits pain by activation of pre and post alpha 2 receptors simulation in
projection neurons of dorsal horn and primary afferents
Uses
• Neuropathic pain
• Cancer pain
Other: Can be used as an adjunct
Antidepressants: TCA – amitriptyline (most common), SNRI – Venlafaxine, duloxetine: MoA, Uses, Other
NE and 5HT reuptake inhibitors promote NE activation of pre and post alpha 2 receptors in projection neurons of dorsal horn and primary afferents
Antidepressant activity may also be important for altering the perceptive part of pain.
Neuropathic pain
Serotonin response required but SSRIs ineffective in Pain!
Antiepileptics: α2δ ligands (gabapentin, pregabalin), Carbamazepine: MoA
α2δ ligands (gabapentin, pregabalin)
• Reduce activation of N and P/Q Ca2+ channels
Carbamazepine
• Stabilizes inactive state of voltage gated sodium channels
Antiepileptics: α2δ ligands (gabapentin, pregabalin), Carbamazepine: Uses
- Neuropathic pain
- Gabapentin
- Post herpetic neuralgia and painful diabetic neuropathy
• Pregabalin
• central neuropathic pain * , fibromyalgia*, postherpetic neuralgia, painful diabetic
neuropathy
• *less effective for these
- Carbamazepine
- Trigeminal Neuralgia 1st line agent
Antiepileptics: α2δ ligands (gabapentin, pregabalin), Carbamazepine: Other
- pregabalin analgesia onset quicker than gabapentin
* Potentiate opioid action (potential for co-abuse)
Others: Topical
- Lidocaine – local anesthetic
- Capsaicin – chilli pepper alkaloid adjunctive
- TRPV1 antagonist
- Ion channel expressed on afferent nociceptors
Others: NMDA Antagonists:
- Ketamine – blocks NMDA and thus glutamate signaling
* See anesthetics lecture
Centrally Active Muscle relaxants: Clinical Uses:
• Centrally acting muscle relaxants are used
primarily as antispasmodics or in the relief of
lower back pain, all of these drugs can interact
with other CNS depressants.
Baclofen (Lioresal) ***Clinical Uses:, Mechanism:
Clinical Uses: Spasticity from various causes, Hiccups
Mechanism:
• GABA-B receptor activator
• Facilitates spinal inhibition of motor neurons
Baclofen (Lioresal) ***Pharmacokinetics etc.
• Takes 3-4 days to work • Peak effect 5-10 days • Rapid oral absorption • Excreted 85% intact (urine and feces)
Baclofen (Lioresal) Main Side Effects
>10% of patients Central nervous system: Drowsiness, vertigo, dizziness, psychiatric disturbances, insomnia, slurred speech, ataxia, hypotonia Neuromuscular & skeletal: Weakness <1% serious effects: Chest Pain, syncope
Other
Baclofen (Lioresal)
• Use with care with other CNS depressants as can enhance the effect. - May be enhanced in the elderly • BOX Warning (see below)
BOX WARNING:
Avoid abrupt withdrawal of the drug; abrupt withdrawal of intrathecal baclofen has resulted in severe sequelae
(hyperpyrexia, obtundation, rebound/exaggerated spasticity, muscle rigidity, and rhabdomyolysis), leading to
organ failure and some fatalities. Risk may be higher in patients with injuries at T-6 or above, history of baclofen
withdrawal, or limited ability to communicate.
BZ –Diazepam ***
see anxiety lecture for mechanism etc.
Clinical use:
• Muscle Spasms – IV or IM
• Muscle relaxant – oral as an adjunct therapy
Carisoprodol (Soma) ** Clinical Uses: Mechanism
Clinical Uses: Acute musculoskeletal
pain
Mechanism • Unknown • Has central depressant action • May work in brain stem
Carisoprodol (Soma) **
Pharmacokinetics
etc. Main Side Effects
• Oral rapid onset (~30 min) • Duration 4-6 hours • CYP2C19 • Active metabolite meprobamate
Anti-cholinergic activity CNS: Drowsiness (13% to 17%) Dizziness (7% to 8%) Headache (3% to 5%) Post marketing reports of many other CNS effects including agitation
Carisoprodol (Soma) ** Other
• Not recommended for use in elderly or in children under 16. • Schedule IV drug do not use for more than 2-3 weeks can induce tolerance and addiction. • Use with caution in patients with history of drug abuse
Chlorzoxazone (Paraflex) *: Clinical Uses, Mechanism
Acute
muscle
Spasms
and pain
• Unknown • Depresses polysynaptic reflexes in the spinal cord and subcortical levels
Chlorzoxazone (Paraflex) *:Pharmacokinetics
etc.
• Oral onset 1 hour • Duration 6-12 hours • Extensive hepatic glucuronidation • Metabolized by multiple CYPs
