ANALGESICS

This chapter focuses on the three first three classes of pain medications.

OBJECTIVES
To be able to discuss the mechanism of action of the drugs under this
classification.
To be able to discuss use and actions of the analgesics.
To be aware on how to manage pain.

1. PAIN AND PAIN MANAGEMENT

-Origin of pain
-Acute and Chronic Pain
-Approaches to pain management

2. OPIOIDS
-Opioid receptor discovery and endogenous ligands
-SARs of Enkephalins
-Opioid receptors
- Drug Monographs

3. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

-Mechanism of Action and NSAID-Induced Side effects
-Structure-Activity Relationships of NSAIDs
-Aspirin and Salicylic Acid Derivatives
-The Conventional Nonselective Cyclooxygenase Inhibitors
-The Selective COX-2 Inhibitors
-The Analgesic Antipyretics: Acetaminophen (Paracetamol) and Related Analogs

4. DISEASE MODIFYING ANTIRHEUMATIC DRUGS

-Synthetic Disease Modifying Antirheumatics drugs

5. DRUGS USED IN THE MANAGEMENT OF GOUT AND HYPERURICEMIA

-Hyperuricemia
-Risk Factors
-Treatment of Acute Gouty Arthritis
-Control of Hyperuricemia

6. TRIPTANS
-Pathophysiology of Migraine
-Structure-Activity Relationship
-Mechanism of Action
-Antimigraine drugs acting on 5-HT 1B/1D Receptors

PAIN AND PAIN MANAGEMENT

Origin of Pain
Major Classification of Pain in its underlying causes;
Physiological (nociceptive)
- most common, and often caused by an injury to body organs ot tissues.
- categorized thought the source of pain; cutaneous pain (skin and surface
tissues), somatic pains (ligaments, tendons, bones, blood vessels), and
visceral pains (body organs and internal cavities).
Inflammatory
-Originates from infection or inflammation as a result of the initial tissue or
organ damage.
Neuropathic
- complex or chronic pain secondary to injury of the Nervous System.
May originate from
- Limb amputation
- Spinal surgery
- Viral infection; shingles
- Worsening of disease states associated with diabetes
- AIDS

ACUTE AND CHRONIC PAIN

Acute Pain
- Mostly a severe type of pain that lasts only until the removal of the source that
causes the pain.
- includes nociceptive, somatic, or visceral pain, postoperative and post traumatic
pain, burn pain, acute pain during childbirth, acute headache, etc.

* Acute and Postoperative pains are often treated using the opioid analgesics.
Chronic Pain
- Lasts longer that 6 months that persists even after the removal of the main
cause
- Divided into:
chronic malignant pain
- (e.g., cancer, HIV/AIDS, amyotrophic lateral sclerosis, multiple sclerosis,
end-stage organ failure)
chronic non-malignant pain
-(e.g., lower-back pain, chronic degenerative arthritis, osteoarthritis,
rheumatoid arthritis, migraine and chronic headache, and bond pain)
- Can be associated by behavioral and psychological factor
- Causes disability among elderly.

APPROACHES TO PAIN MANAGEMENT

-Access to Controlled Medication Programs is the formulated series of guidelines
for pain management by The World Health Organization.

-Three-step analgesic ladder is the guideline that permits a physician to select

the most appropriate drug treatment regimen for the patients.

-The choice of analgesic therapy must be based on the pain intensity. E.g.,
Acetaminophen and NSAID's are both used individually for mild pains.
 OPIOIDS
Goldstien et al
- found that radiolabeled levorphanol bound stereospecifically to certain mouse
brain function.
Pert
- was able to show that the pharmacologic potencies of the opioid drugs were
proportional to their ability to compete with the antagonist for opioid receptor
binding.

Hughes 1975
- confirmed the existence of an opioid receptor and intensified the SAR studies of
the analgesic opioids.

SAR'S OF ENKENPHALINS
TYR1
- changes to this amino acid is either by substituting with other amino acids
or masking the phenolic hydroxyl (OH) or amino acids, produce an
inactive or weakly active peptide.
GLY2
- selective omega-agonist
GLY3
- Almost all changes to this amino acid result in a drop in potency.
PHE4
- Para substitutions with electron donating, hydrophillic functional groups
(e.g., NH2 and OH) abolish activity.
MET5/LEU5
- More potent than enkephalins in both in vivo and in vitro tests.

OPIOID RECEPTORS
- are distributed throughout the brain, spinal chord and peripheral tissues.
The Mu RECEPTOR
- Are found primarily in the brain stem an medial thalamus.
- In general, agonists at the Mu-receptor produce analgesia, respiratory
depression, decreased gastrointestinal motility, euphoria, feeding and the
release of hormones.
The Omega RECEPTOR
- Utilizes the "address-message" concept proposes that one part of the
molecule may act as an "address", essentially directing the chemical to
the correct receptor by binding specifically to that receptor, and
another part of the molecule acts as a "message", which gives the
compound the biological action.
The K- RECEPTOR
- Are primarily found in the limbic, brain stem, and spinal cord
THE ORPHANIN RECEPTOR/FQ/NOP1
- Composed of 17 amino peptide, can reverse the analgesic effects of
morphine thus is anti opioid in some situations.
 DRUG MONOGRAPHS
4,5- Epoxymorphinans
- MORPHINE is a prototype u-receptor agonist, used in severe and no
relief from NSAID's and a less potent drug.
-CODEINE is a naturally occuring alkaloid in opium, the general
pharmacological action is similar ro morphine but does not possess the
same analgesic potency.
- HEROIN alternate analgesic to morphine.
-HYDROMORPHONE , a synthetic derivative of morphine , 5 times as
potent as morphine.
- HYDROCODONE ~available as anticholinergic agent but it already
discouraged due ro misuse.
- OXYCODONE is synthesized from natural opium alkaloids.
-OXYMORPHONE is more potent than injectable hydromorphone via
dosage.
Morphinanns
- LEVOPHANOL, its analgesic effect does not match the long plasma half-life
which is 6 to 8 hrs.
-DEXTROMETHORPHAN is the dextrorotatory form of levorphanol with a
methoxy group on the 3-position ring.
Benzomorphans
- PENTAZOCINE is the only benzomorphan in clinical use.
4- phenylpiredines and 4-Anilopiperidines
- MEPERIDINE has low potency at the receptor compare with morphine but
much higher penetration to brain resulting in a compound with about 10% of
potency of morphine.
-DIPHENOXYLATE is a weak opioid agonist
- LOPERAMIDE inhibits acetylcholine which results to reduction of fecal
matter.
-FENTANYL is beneficial for patients with chronic pain that ate unable to
take oral medication because it is usually formulated as a transdermal patch.
- ALFENTANYL is used as an analgesic adjunct of general anesthesia and to
maintain analgesia during general surgical procedures.
- SUFENTANIL is 7 times more potent tha fentanyl with an immediate onset
of action.
-REMIFENTANYL used for induction and maintenance of surgical
anesthesia.
Diphenylheptanes
- METHADONES is a synthetic opioid approved for its analgesic therapy and
maintenance and therapy of opioid addiction.
-PROPOXYPHENE is a derivative of methadone, more potent analgesic than
aspirin, acetaminophen at lower dose.
Miscellaneous
- TRAMADOL analgesic with multiple mechanism of action.
-NALBUPHINE, at low parenteral doses, it has 2/3 analgesic potency as
morphine.
- BUTORPHANOL is an agonist of k-receptor but partial agonist and partial
antagonist of u-receptor
 -BUPRENUORPHINE is a synthetic, highly lipophilic opiate derived from
thebaine.
Opioid Antagonist
- NALOXONE pure antagonist of all receptor subtypes.
-NALMEFENE pure opioid antagonist.
- METHYLNALTREXONE antagonists only at peripheral opioid receptors.

NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS
Mechanism of Action and NSAID-Induced side Effects.
1971, Vane
-is the first one to identify the cyclooxygenases as the molecular target of
NSAID's. Cyclooxygenase also known as prostaglandin endopoxide synthase
or PGH synthase is the rate limiting enzyme responsible for the biosynthesis
of PG's.
PG's
- role is regulation of pain, inflammation, gastric acid secretion, wound
healing and renal function, thus, blockage of PGH2 production prevents its
further conversion bu specific terminal prostaglandin synthase or isomerase.

-NSAID's in the parietal cell

-removes its ability to modulate histamine-mediated release of gastric
acid from the pareital cell
-whereas blockage of PGI2 and PGI3 synthesis in the epithelial cell in the
stomach linings
-prevents their action on the biosynthesis and release of bicarbonate and
mucous gel desperately needed to repair damage resulting from erosion
of gastric acid.

STRUCTURE- ACTIVITY RELATIONSHIPS OF NSAID'S

The therapeutic potency of the conventional NSAID's are highly correlated
with their ability to induce upper GI toxicity.
- Enzymatic Structure of Cyclooxygenases
- Binding of NSAID's to CYCLOOXYGENASE
-BINDING OF CELECOXIB TO COX-2 ISOZYME
-PIROXIC AND MELOXICAM: THE DIFFERENCE IN THEIR COX
SELECTIVITY
- ASPIRIN AND ITS COX-1 SELECTIVITY

ASPIRIN AND SALICYLIC ACID DERIVATIVES

- are the first groups of NSAID's introduced to medicine for their use as
analgesics to relieve pain and antypyretics to reduce fever.
- children of 3 and 12, who are recovering from chicken pox or flu should not
be given aspirin as it could further develop as rare disease known as Reye's
syndrome.

THE CONVENTIONAL NONSELECTIVE CYCLOOXYGENASE

INHIBITORS
 - The conventional NSAID's, being more potent than aspirin and related
salicylates , are the drug of choice for the treatment of RA and other
inflammatory disease.
- The conventional NSAID's vary considerably in terms of their selective
inhibitory action for COX-2 relative to COX-1 isozymes and also relative
drug induced toxicities.
THE SELECTIVE COX-2 INHIBITORS
Were introduced worldwide, disregarding the cardiovascular safety issue:
-Celecoxib, Rofecoxib (by Vane's hypothesis), Valdecoxib, Etoricoxib,
Parecoxib Sodium

-Rofecoxib is withdrawn due to failure of safety identified through

clinical trials.
THE ANALGESIC ANTIPYRETICS: ACETAMENOPHEN
(PARACETAMOL) AND RELATED ANALOGS
-most widely known analgesic/antipyretic for its ability to relieve the pain as
well as reducing fever because, unlike aspirin and salicylates, they do not
cause ulceration or increase bleeding time, making acetaminophen better drug
of choice as analgesic and antipyretic.
- Phenacetin, once more popular than acetamenophen but it was more
susceptible to cause renal and urinary tract tumors using experimental animal
models.

DISEASE MODIFYING ANTIRHEUMATIC

DRUGS
RA
- one of the most common chronic, anti-inflammatory autoimmune diseases, affecting
approximately % of the worlds adult population.

- characterized by persistent inflammation of the synovial lining of the joints that

causes pain, swelling, and stiffness of the upper and lower extremities.

- if left untreated, can lead to permanent joint cartilage and bone damage that
eventually results in disability and a significant impairment of quality of life.

- Treatment:
combination of physical and other drug therapy including
a) aspirin,
b) other NSAIDs
c) Glucocorticoids- initially to provide symptomatic relief of pain and swelling
d) DMARDs drugs- slow down the underlying disease progression and to limit
further joint damage
- slow-acting antirheumatic drugs
- methotrexate, hydroxychloroquine, sulfasalazine, leflunomide
etc.
SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

Methotrexate (MTX, Rheumatrex)

-antifolate drug used in cancer treatment
-also been used in the disease management of RA
-first line therapy for RA patients who are not responsive to NSAIDs alone
- Four anti-inflammatory MOA:
Prevents antigen-dependent T-cell proliferation by blocking de novo pyrimidine
biosynthesis, via a reversible inhibition of dihydrofolate reductase
Inhibits folate-mediated production of spermine and spermidine in synovial
tissue.
Reduce intracellular glutathione concentration, thereby altering the cellular redox
state that suppresses the formation of reactive oxygen radicals in synovial tissue.
Inhibit osteoclastogenesis (I.e., bone erosion) in patients with RA, by modulating
the interaction of the receptor activator of nuclear factor KB , its ligand, and
osteoprotegrin.

Hydroxychloroquine and Chloroquine (Plaquenil, Quineprox)

-older drug used to treat malaria used more often in the treatment of RA
and lupus erythematosus.
-Ability to interfere w/ lipopolysaccharide-induced TNF-a gene expression,
thereby preventing TNF-a release from mononuclear phagocytes.

Sulfasalazine (Azufidine)
-used for the treatment of RA or ankylosing spondylitis, and inflammatory
bowel diseases (IBDs) such as ulcerative colitis and Chron disease.
-5-ASA - active metabolite
- believed to work, via similar mechanisms of action to the salicylates
by blocking prostaglandin synthesis in the lower intestine.

-Inhibits neutrophil function, reduces imunoglobulin levels, and interferes w/

T-cell function via suppression of NF-KB activation.

Leflunomide (Arava)
-an isozaxole prodrug, is an orally active DMARD marketed in 1998 for
the treatment of RA.
-Active metabolite: 2-cyano-3-hydroxy-2-butenamide (teriflunomide)
-Teriflunomide- blocks T-cell proliferation by inihibiting dihydroorotate
dehydrogenase, the rate limiting enzyme in the de novo
biosynthesis of pyrimidine that is believed to be
responsible for the immunosuppressive properties
leflunomide.

-several cases of toxic neuropathy have been observed during its use, thus
careful monitoring of the patients neurological status during treatment is
mandatory.

The Gold Compounds

- Effective in the treatment of RA:
a) Gold salts
b) Gold Sodium thiomalate (Aurolate)
c) Aurothioglucose (Solganal)
d) Auranofin (Ridaura)

Other Disease-Modifying Antirheumatic Drugs

Penicillamine (Cuprimine) - metabolite of penicillin
Chlorambucil (Leukeran)- cytotoxic anticancer drug
Azathioprine (Imuran)-
Cycophosphamide (Cytoxan)
Cyclosporine ( Sandimmune) - immunosuppressants
Mycophenolate mofetil ( MMF)

DRUGS USED IN THE MANAGEMENT OF

GOUT AND HYPERURICEMIA
Gout
- one of the most common causes of acute inflammatory arthritis in men older
than 40 years old, characterized by the deposition of monosodium urate
crystals in the joints and cartilage.

- Phagocytosis of urate crystals by human neutrophils (and macrophage)

-induces synthesis and release of a GLYCOPROTEIN, the crystals
induced chemotactic factor (CCF)

- believed to be the inital stimulus in the development of acute gouty

attacks
Hyperuricemia
-having serum uric acid levels greater than 7.0 mg/dL in men or more than 6.0
mg/dL in women.

Risk Factors

- Other factors that may also increase the risk of development of gout includes:
a) HYPERTENSION
b) RENALS SUFFICIENCY
c) OBESITY
d) USE OF THIAZIDES OR LOOP DIURETICS
e) HIGH INTAKE OF ALCOHOLIC BEVERAGES
f) PURINE RICH FOODS (meats, liver, bacon, fish and beans)

Control of hyperuricemia

-By maintaining serum urate levels below the limit of solubility (I.e., at 6 mg/dL
or lower) with drugs that block uric acid synthesis by inhibiting xanthine oxidase
or with uricosuric drugs that promote uric acid elimination from the renal
tubules.
 Treatment of Acute Gouty Arthritis
-Colchicine
- ability to block the production and release of the CCF that mediates the
inflammatory response because of urate crystals, a mechanism different
from colchicines antimitotic action which is being investigated for its
anticancer properties.

TRIPTANS
- are safe and effective drugs for abortive , but not for prohylactic, treatment of
moderate to severe migraine and cluster headaches.

Pathopyshiology of Migraine

- Migraine- a recurrent and debilitating headache disorder affects about 12% of

the worldwide population with a higher prevalence in women (~18%)
than in men (~6%)

- Symptoms: Nausea, vomiting , sensitivity to light (photophobia),

sound (phonophobia), or movements that can also severely impact
their quality of life).

THE VASCULAR THEORY OF MIGRAINES

- The vasodilation of cranial carotid arteriovenous anastomosomes (sites of many
5-HT 1B/1D receptors) and meningeal, dural, cerebral, or pial vessels (primary
sites of 5-HT 1B/1D receptors) plays an important role in the pathogenesis of
migraines and is responsible for the pain associated with migraine headaches.

THE NEUROGENIC INFLAMMATION THEORY OF MIGRAINES

- Suggests that migraine occurs as a result of an abnormal firing of meningeal
nociceptors at the TGVS.

- Activation of trigeminal neurons releases vasoactive peptides including

calcitonin gene-related peptide (CGRP, a vasodilator peptide), substance P, and
neurokinin A (both play an important role in pain transmission as well as
activation of immune responses and neurogenic inflammation) onto dural tissue
where these peptides produce a local response known as neurogenic
inflammation.

Structure-Activity Relationship
All clinically available triptans possess comparable pharmacodynamic properties.
They all bind and stimulate serotonin 5-HT1B/1D with affinity in the low
nanomolar ranges, thus they are equally effective for the acute treatment of
migraine.2
they are not equally efficacious in preventing migraine recurrence because of the
differences in their elimination half-lives
They also differ in their potential to induce drug-related CNS side effects,
especially somnolence and paresthesia that may lead to a patients noncompliance
of an otherwise effective migraine treatment.2
MOA
Three distinct mechanisms have been suggested to explain the actions of triptans:
(a) Triptans abort migraine headache by its agonist action at the 5-HT1B
receptors, thereby inducing vasoconstriction of the meningeal, dural,
or pial blood vessels.
(b) Triptans also inhibit neurogenic inflammation via its presynaptic stimulation
of 5-HT1D receptors and/or through its additional action at the 5-HT1B/1D
receptors.
(c) Triptans relieve migraine pain transmission most likely because of its
inhibitory action at the trigeminal pain pathway mediated via 5-HT1B/1D/1F
receptors.

Antimigraine Drugs Acting on 5-HT 1B/1D Receptors

SUMATRIPTAN (IMITREX)
-the first triptan approved (1991) for the acute treatment of migraine headaches.
-has a very fast onset of action via SC injection or nasal spray administration.
-contraindicated with monoamine oxidase inhibitors because it is primarily degraded
by hepatic MAO-A.

ZOLMITRIPTAN (ZOMIG, ZOMIG-ZMT)

-the second triptan marketed (approved in 1997), has a much better
bioavailability (40%48%) than sumatriptan.
- rapidly absorbed after oral or nasal spray administration

NARATRIPTAN (AMERGE, NARAMIG)

-the third triptan approved in 1998, is one of the most lipophilic triptans marketed
to date.
-has a much improved bioavailability (63% in men and 74% in women), a greater
affinity for 5-HT1B/1D receptors (36 times), and a lower recurrence rate than
sumatriptan because of its much longer elimination half-life.

RIZATRIPTAN (MAXALT)
-is a fast-acting triptan because of its moderate lipophilicity yet has a very short
elimination half-life similar to sumatriptan (i.e., like sumatriptan, it is mainly
metabolized by MAO-A).
-has a slightly faster onset and that it has an orally disintegrating tablet
formulation which can be taken without water.

ALMOTRIPTAN (AXERT)
- has the highest oral bioavailability among all triptans
- metabolized by both MAO-A and CYP3A4, thus has a more favorable side
effects profile when compared with sumatriptan.

FROVATRIPTAN (FROVA)
-a newer triptan introduced into the market in 2001.
- has the highest affinity for brain 5- HT1B receptors and the longest elimination
half-life among all triptans.
 - disadvantage of this drug is its slower onset of action because of its greater
water solubility.
- drug of choice for patients with longlasting migraines or if recurrence is a
problem.
ELETRIPTAN (RELPAX)
- the newest triptan with highest affinity for 5-HT1B, 5-HT1D, and 5-HT1F
receptors.