Drugs For Pain

Front 1

Stimulation

Back 1

Injury causes release of chemicals that sensitize
or stimulate nociceptors

Front 2

Transmission

Back 2

The signal continues from the site of noxious stimulus and enters the substantia gelantinosa of the dorsal horn of the spinal cord and then ascends to higher centers in the CNS. The neurons which conduct information to the CNS include Aδ fibers (rapid transmission of sharp, painful stimuli) and C-fibers (slower transmission resulting in dull, aching sensation).

Front 3

Perception

Back 3

Conscious experience of pain

Front 4

Modulation

Back 4

Neurons from the brain stem descend to the spinal cord and release substances such as endogenous opioids, norepinephrine, and serotonin
that inhibit transmission.

Front 5

Inhibitors of cyclooxygenase---Mechanism of action

Back 5

1. By inhibiting the activity of cyclooxygenase, prostaglandin production is reduced which reduces the local inflammatory response and peripheral sensitization.
2. Inhibitors of COX that cross the blood-brain barrier prevent the generation of prostaglandins that act as pain-producing neuromodulators in the spinal
cord dorsal horn.

Front 6

Inhibitors of cyclooxygenase--Specific drugs

Back 6

Aspirin, Ibuprofen, and acetaminophen were discussed in detail in other presentations

Front 7

Naproxen

Back 7

a. Same chemical class (propionic acid) as ibuprofen.
b. Compared to ibuprofen, naproxen is more potent and has a longer half-life; therefore, it can be administered less frequently with equivalent analgesic efficacy.

Front 8

Celecoxib

Back 8

a. A COX-2 selective NSAID
b. Causes less severe GI toxicity than non-selective NSAIDs. Other adverse effects are similar to those of non-selective NSAIDs.
c. The COX-2 inhibitors rofecoxib and valdecoxib were voluntarilymwithdrawn from the market after prospective studies demonstrated an increase in thrombotic events associated with their use. While the mechanism of this increase remains unclear, it may be the result of greater inhibition of anticoagulant prostaglandins than of prothrombotic prostaglandins. Celecoxib, which has relatively less COX-2 selectivity, does not appear to increase the incidence of cardiovascular events compared to placebo or non-selective NSAIDs.
d. Alternative to use of a selective COX-2 inhibitor, coadministration of the PGE1 analog, misoprostol, or proton pump inhibitors (e.g., omeprazole), in conjunction with NSAIDs can prevent duodenal and
gastric ulceration.

Front 9

Morphine--type

Back 9

opiod, strong, full agonist...the prototypical opioid and the one to which others are compared

Front 10

Morphine--Mech of Action (molecular events)

Back 10

(a) Opioids receptors (mu, delta, and kappa) are G-protein coupled receptors. When they are activated calcium entry into the nerve ending is inhibited (Go inhibits calcium channels) and potassium channels are opened leading to efflux of potassium and hyperpolarization of the membrane (Gi activates K+ channels).
(b) Calcium is needed in order for release of neurotransmitters. Thus, inhibiting calcium entry into a nerve ending inhibits
the release of neurotransmitters. When membranes are hyperpolarized, they are resistant to activation caused by, for example, neurotransmitters such as substance P. Together, these molecular mechanisms inhibit pain transmission.

Front 11

Morphine--Mechanism of action (analgesia)

Back 11

(a) Two components
i) Somatic/visceral effects
Opioids decrease release of nociceptive peptides and inhibit postsynaptic activation
ii) Affective
Opioids alter emotional aspects of pain in the cerebrocortex. They decrease pain perception, and increase euphoria and sleep
(b) Tolerance develops (see below)

Front 12

Morphine--Mech of Action (Antitussive)

Back 12

Morphine and related opioids depress the cough reflex at least in part by a direct effect on a cough center in the medulla.

Front 13

Morphine---Tolerance

Back 13

Repeated use of a constant dose of a drug results in a decreased therapeutic effect. The development of tolerance requires either a change of analgesic drug or an increase in the dose or frequency of
administration to maintain analgesia.

Front 14

Morphine--Admin and Elim

Back 14

i. Morphine can be given parenterally, orally, or rectally.
ii. Metabolized in the liver (undergoes extensive first-pass metabolism upon oral administration)

Front 15

Morphine--Adverse Effects

Back 15

LOOK MORE INTO THESE ON HANDOUT
-Medullary Effects (decr respiration, vomitting, tolerance)
-Miosis
-Constipation
-Biliary Colic
-Release of Histamine
-Physical Dependence

Front 16

Morphine--Contraindications

Back 16

May want to read more in Handout
--Pts w/ hepatic disease (opioids metab'd by liver->liver disease= incr bioavailability (oral or cumulative doses)
--Pts w/ renal disease (accum of m'lites may cause CNS and other side effects)
--Pts w/ pulmonary disease (depressant and histamine)
--Pts w/ head trauma (opioid incr ICP, miotic effect as opioid depress pupilary reflex for dx of concussion)

Front 17

Morphine--Drug interactions

Back 17

Other sedatives (e.g., alcohol and barbiturates) in combination with opioids can increase sedation and decrease respiration

Front 18

Meperidine--info

Back 18

Strong opioid , full agonist
a. Less antitussive and constipating effects-good for patients with
pulmonary disease
b. Metabolized to normeperidine which has proconvulsant and hallucinogenic effects

Front 19

Meperidine--Contraindications

Back 19

i. Decreased renal function (normeperidine accumulates)
ii. Liver disease (meperidine accumulates)
iii. Patients with seizures (since drug and normeperidine can cause seizures)

Front 20

Fentanyl--Admin/Info

Back 20

Strong opioid, agonist
Available for administration as via a transdermal patch

Front 21

Fentanyl--Side Effects

Back 21

All side effects of morphine
i. Greater intensity (80–100X morphine)
ii. Shorter duration of action
Adverse effects, contraindications and precautions: same as morphine

Front 22

Methadone

Back 22

Strong agonist
Same as morphine but longer duration of action and better oral bioavailability

Front 23

Oxycodone

Back 23

a. Oxycodone, a semi-synthetic derivative of morphine, is only available in oral formulations.
b. Same as morphine but more about twice as potent.

Front 24

Codeine--metab and use

Back 24

weak opioid agonist
a. Metabolized to morphine which contributes to analgesia
b. Used with nonopioids
i. Decrease amount of opioid
ii. Decrease pain by two different mechanisms
c. Used for antitussive effects

Front 25

Tramadol

Back 25

weak opioid agonist
a. A centrally-acting opioid agonist and blocks reuptake of norepinephrine and serotonin
b. Increased risk of seizures in patients at risk for seizures (e.g., head trauma, CNS infection) or patients taking SSRIs, drugs which lower seizure threshold or drugs which inhibit metabolism of tramadol (drugs inhibiting P450 enzymes)
c. Increased risk of serotonin syndrome in patients taking SSRIs, SNRIs, triptans, or St. John’s wort concurrently.

Front 26

Pentazocine--1. Mechanism of action

Back 26

a. Mixed agonist (κ)/antagonist (μ)
b. Potent opioid effect in naive patients but precipitates withdrawal in those patients who are physically dependent

Front 27

Pentazocine--Admin

Back 27

Administered orally with naloxone to prevent abuse (naloxone is inactivated orally but will block effects of drug when administered IV)

Front 28

Pentazocine--Adverse Effects

Back 28

a. Psychotomimetic (e.g., hallucinations)
b. Hypertension and tachycardia

Front 29

Buprenorphine

Back 29

1. A partial agonist at μ-opioid receptors
2. Potent opioid in naive patients but can precipitate withdrawal in those patient who are physically dependent
3. Administered intravenously or orally.
4. Used for analgesia and treatment of opioid addiction. Available orally in combination with naloxone for treatment of opioid addiction.
5. Adverse effects similar to morphine

Front 30

Opioid receptor antagonists (Naloxone)
1. Mechanism of action

Back 30

a. Pure antagonist
b. Blocks opioid effects at all receptor subtypes
c. Precipitates withdrawal (no effects in non-addicted patients)

Front 31

Opioid receptor antagonists (Naloxone)--Used for overdose

Back 31

a. Fast onset IV but fast offset as well
b. Administer until opioid is eliminated
c. Reverses respiratory depression in neonates born to mothers who used opioids

Front 32

Effects of naloxone in reversing opioid effects

Back 32

Small doses (0.4 to 0.8 mg) of naloxone given intramuscularly or intravenously prevent or promptly reverse the effects of μ receptor agonists. In patients with respiratory depression, an increase in respiratory rate is seen within 1 or 2 minutes. Sedative effects are reversed, and blood pressure, if depressed, returns to normal. The duration of action of naloxone is relatively short, and it often must be given repeatedly or by
continuous infusion.

Front 33

Amitriptyline

Back 33

Adjuvant Analgesics--
1. Tricyclic antidepressants such as amitriptyline can relieve many types of neuropathic pain.
2. The analgesic effect of amitriptyline is thought to come from its ability to inhibit norepinephrine reuptake. Similar to opioid receptor activation, the increase in concentration of NE results in a decrease of calcium entry and an increase potassium efflux. Ultimately, there is an inhibition of nociceptive transmission.

Front 34

Gabapentin

Back 34

1. Anticonvulsants such as gabapentin have been effective in controlling neuropathic pain.
2. Gabapentin binds to voltage-gated Ca++ channels which reduces neuronal activity and pain in patients. The mechanism whereby binding to these channels reduces neuronal activity is not known.

Front 35

Duloxetine and milnacipran--treatment

Back 35

Antidepressants such as duloxetine are used in the treatment of
neuropathic pain.

Front 36

Duloxetine and milnacipran--Activity

Back 36

Duloxetine and milnacipran are inhibitors of reuptake of norepinephrine and serotonin.
a. The mechanism whereby inhibition of reuptake of NE inhibits nociceptive transmission is similar to that described above for amitriptyline.
b. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are not effective analgesics. However, when NE uptake is inhibited, inhibition of serotonin reuptake is able to produce analgesia.

Front 37

Fibromyalgia treatment

Back 37

Duloxetine and milnacipran are approved for treatment of pain in patients with fibromyalgia.