Download TOLERANCE

Pain
• TWO CLASSES OF DRUGS ARE USED TO REDUCE PAIN
OR THE AWARENESS OF PAIN: ANESTHETICS
(MEANING WITHOUT SENSIBILITY), HAVE THIS
EFFECT BY REDUCING AWARENESS OR BY
BLOCKING CONSCIOUSNESS COMPLETELY.
• THE BARBITURATES AND VOLATILE ANESTHETICS,
SUCH AS ETHER, ARE EXAMPLES OF THIS TYPE OF
AGENT.
• SECOND CLASS IS THE ANALGESICS (MEANING
WITHOUT PAIN). THEY REDUCE PAIN WITHOUT
CAUSING A LOSS OF THE SENSES.
• VISCERAL PAIN, SUCH AS INTESTINAL
CRAMPS, ARISES FROM NONSKELETAL
PORTIONS OF THE BODY.
• OPIATES ARE EFFECTIVE IN REDUCING
PAIN OF THIS TYPE.
Opium
HISTORY
-DERIVED FROM POPPY PLANT Papavera somniferum. NO TRULY
WILD POPULATIONS OF THIS ACTUALLY EXIST. IT WAS
SELECTIVELY BRED FROM Papavera setigerum AND EXTENSIVELY
CULTIVATED.
NO ONE KNOWS WHERE THE PLANT ORIGINATED.
THOUSANDS OF KNOWN VARIETIES OF POPPIES, ONLY ONE HAS
OPIUM.
-HISTORY OF MEDICAL USE FOR 6000 YEARS
-SINCE ALSO PRODUCED EUPHORIA AND RELIEVED ANXIETY,
LEAD TO EXTENSIVE RECREATIONAL USE
-ANNUAL PLANT...3-4 FT. HIGH WITH LARGE FLOWERS 4-5
INCHES IN DIAMETER...FLOWERS MAY BE WHITE, PINK, RED,
PURPLE, OR VIOLET
-OPIUM IS PRODUCED AND AVAILABLE FOR
COLLECTION FOR ONLY A FEW DAYS, BETWEEN
THE TIME THE PETALS DROP AND BEFORE THE
SEED POD MATURES
COLLECTION IS HIGHLY LABOR INTENSIVE.
-TO HARVEST, SHALLOW CUTS ARE MADE INTO, BUT
NOT THROUGH, THE UNRIPE SEED POD.....AT DUSK
-DURING NIGHT, WHITE SUBSTANCE OOZES FROM
THE CUTS, OXIDIZES TO A RED-BROWN COLOR, AND
BECOMES GUMMY
-IN MORNING, RESINOUS SUBSTANCE IS SCRAPED
AND COLLECTED...
WORD OPIUM IS FROM GREEK MEANING "JUICE"
POPPY SEEDS FOUND IN NEOLITHIC
EUROPEAN SITES FROM 5000 BC.
-SUMERIANS (BABYLONIANS) CARVED
TABLETS WITH PICTURES OF POPPY 2600
BC. WITH INSCRIPTION HUL "JOY" AND GIL
"PLANT".
MORPHINE HAS BEEN FOUND IN THEBAN
(EGYPTIAN) FUNERAL POTS FROM 1500 BC.
-IN CLASSICAL LITERATURE OF VIRGIL,
SOMNUS, THE ROMAN GOD OF SLEEP,
WAS DESCRIBED AS BEING ADORNED
WITH OR CARRIED POPPIES AND
SOMETIMES AN OPIUM CONTAINER
-LIKE SANDMAN OF TODAY, SOMNUS WAS
PICTURED POURING JUICE FROM THE
CONTAINER INTO THE EYES OF THE
SLEEPER
-CHINESE LEGEND HAS THE POPPY
PLANT SPRINGING UP FROM THE
EARTH WHERE BUDDHA'S EYELIDS
FELL WHEN HE CUT THEM OFF TO
PREVENT SLEEP
FIRST SPECIFIC MEDICAL USE OF
OPIUM:
EBERS PAPYRUS (1500 B.C.) CALLS IT
REMEDY TO PREVENT THE
EXCESSIVE CRYING OF CHILDREN.
LAUDANUM, DEVELOPED BY DR. THOMAS
SYDENHAM -CONTAINED "2 OZ STRAINED OPIUM, 1
OZ SAFFRON, AND A DRAM OF CINNAMON AND OF
CLOVES DISSOLVED IN A PINT OF CANARY WINE AND
TAKEN IN SMALL QUANTITIES"
-HE HIGHLY ADVOCATED THE USE OF OPIUM
1680: "I CANNOT FORBEAR MENTIONING WITH
GRATITUDE THE GOODNESS OF
THE SUPREME BEING, WHO HAS
SUPPLIED AFFLICTED MANKIND
WITH OPIATES FOR THEIR RELIEF..“
-19TH CENTURY - OPIUM USE BECAME BIG WITH
ENGLISH AND FRENCH WRITERS
-THOMAS DEQUINCY..PURCHASED LAUDANUM
FOR TOOTHACHE..SPENT REST OF LIFE
TAKING THE DRUG AND WRITING ABOUT HIS
EXPERIENCES WITH IT.
"I took it, and in an hour, Oh Heavans !
What a revulsion ! What an upheaving,
from its lowest depths, of the inner spirit 1
What an apocalypse of the world within
me. What had opened before me -- an
abyss of divine enjoyment suddenly
revealed. Here was a panacea for all
human woes. Here was the secret of
happiness, about which philosophers had
disputed for so many ages, at once
discovered".
Thomas de Quincey (1785-1859)
-ELIZABETH BARRETT
BROWNING...ADDICTED TO LAUDANUM
-SAMUEL TAYLOR COLERIDGE'S "KUBLA
KHAN" WAS SAID TO HAVE BEEN CONCEIVED
AND COMPOSED IN AN OPIUM REVERIE AND
THEN WRITTEN DOWN AS BEST AS HE
COULD REMEMBER IT,
UNTIL THE DOORBELL RANG AND HE WAS
NEVER ABLE TO FINISH HIS WORK.
AFTER WWII, PAREGORIC, A COMBINATION
OF OPIUM AND CAMPHOR, WAS USED TO
TREAT DIARRHEA IN INFANTS!
HISTORICAL BIOCHEMISTRY
-ABOUT 1806, A GERMAN YOUTH,
FREDERICH SERTURNER, ISOLATED
THE PRIMARY ACTIVE INGREDIENT IN
OPIUM.
HE TESTED THE NEW DRUG ON HIS
FRIENDS AT 10 TIMES THE MODERN
RECOMMENDED DOSE!
-ACTIVE AGENT WAS 10X MORE
POTENT THAN OPIUM
-HE NAMED IT MORPHIUM AFTER
MORPHIUS, THE GOD OF DREAMS
MORPHIUS
-LATER WORK FOUND OVER 30 DIFFERENT
ALKALOIDS OF OPIUM, WITH THE SECOND
MOST IMPORTANT ONE BEING ISOLATED IN
1832 AND NAMED CODEINE,
THE GREEK WORD FOR "POPPY HEAD"
-1874- 2 ACETYL GROUPS WERE
ATTACHED TO MORPHINE BY CHEMISTS
YIELDING HEROIN
-PLACED ON THE MARKET IN 1898 BY
BAYER LABS AS A NONADDICTING
SUBSTITUTE FOR CODEINE!
-CHEMICAL CHANGE WAS IMPORTANT
BECAUSE HEROIN IS ABOUT 3X AS
POTENT AS MORPHINE
-2 ACETLY GROUPS INCREASE LIPID
SOLUBILITY...ENTERS BRAIN MORE
RAPIDLY
Aspirin is derived from A = Acetyl and "Spirsäure" = an old
(German) name for salicylic acid
PHARMACODYNAMICS:
-MORPHINE IS READILY ABSORBED THROUGH
MOST MUCOUS MEMBRANES:
NASAL MUCOSA - HEROIN CAN BE SNORTED
VIA THE LUNGS - WHEN OPIUM IS SMOKED
-ADMINISTERED MOST COMMONLY BY
SUBCUTANEOUS INJECTION, ALTHOUGH ORAL
ADMINISTRATION IS NOT UNCOMMON
-ONCE ABSORBED, DISTRIBUTION IS FAIRLY
UNIFORM IN MOST TISSUES
-ALTHOUGH IT HAS GREATEST EFFECTS ON
CNS, MORPINE DOES NOT CONCENTRATE
THERE
-IN FACT, ONLY SMALL QUANTITY CAN CROSS
BBB
LATENCY AND DURATION
MORPHINE
CODEINE
HEROIN
EQUIANALGESIC DOSE
(SUBCUTANEOUS)
10MG
120MG
3-4MG
LATENCY
30-60MIN
30-60MIN
15MIN
DURATION
4-5HR
2-4HR
4-5HR
SMALL TO MODERATE DOSE (5-10MG)
-PSYCHOLOGICAL EFFECTS -DROWSINESS
-DECREASED SENSITIVITY TO EXTERNAL AND
INTERNAL STIMULI
-LOSS OF ANXIETY
-LOSS OF INHIBITION
-PHYSIOLOGICAL EFFECTS -MUSCLE
RELAXATION, RELIEF OF PAIN, DEPRESSED
RESPIRATION, CONSTRICTED PUPILS, NAUSEA
(EVEN AT SMALL DOSE), INABILITY TO
CONCENTRATE, FOLLOWED BY DREAMY
SLEEP
HYPOTENSION - MORPHINE RELEASES
HISTAMINE IN THE BLOOD.
- ALSO DECREASES COUGH REFLEX - CODEINE
PRIMARILY USED AS COUGH SUPPRESSANT
AT SLIGHTLY HIGHER DOSES
-ABNORMAL STATE OF ELATION OR EUPHORIA THAT
IS DIFFERENT FROM THE USUAL SENSE OF
WELL-BEING...MORE INTENSE
-IF INJECTED IV, RESULTS IN THE KICK, BANG, OR
RUSH...DESCRIBED AS AN ABDOMINAL ORGASM, A
SUDDEN FLUSH OF WARMTH LOCALIZED IN THE PIT
OF THE STOMACH...NO RUSH IF SMOKED, SNIFFED,
SWALLOWED, OR INJECTED SUBCUTANEOUSLY
(INITIALLY THOUGHT ADDICTION WAS DUE TO THIS
RUSH, BUT CAN BE ADDICTED WITHOUT MAINLINING)
-UNLIKE OTHER EUPHORIC DRUGS (E.G. MUSHROOMS
OR LSD), NO HALLUCINATIONS FOR MORPHINE.
IN CONTRAST, UNREFINED AND PURE OPIUM IS HIGHLY
HALLUCINOGENIC.
-AT HIGHEST DOSES, DEPRESSION DEEPENS INTO
UNCONSCIOUSNESS
-PUPILS FURTHER CONSTRICT (PIN-POINT PUPILS)... MAY
BE MISLEADING. OPIATES ACTUALLY PRODUCED
WHAT IS CALLED "HIPPUS" OR THE FLUCTUATION OF
PUPIL SIZE. PUPILS ARE OCCASSIONALLY PIN-POINT
AND OCCASSIONALLY DILATED.
- SEVERE RESPIRATORY DEPRESSION (ULTIMATE CAUSE
OF DEATH)
-IMPAIRED HOMEOSTATIC FUNCTIONS...E.G.BODY TEMP
FLUCTUATES
-FLUID RETENTION
-DECREASED HORMONAL OUTPUT FROM PITUITARY
-SLURRED SPEECH, PSYCHOMOTOR RETARDATION,
MENTAL CLOUDING
PURE ANTAGONISTS- NALOXONE (NARCAN)...
NO MORPHINE-LIKE EFFECTS...REVERSE EFFECTS OF
THE NARCOTIC ALREADY THERE...USED IN
EMERGENCY ROOM TO REVERSE EFFECTS OF
OVERDOSE OF OPIUM
AND THE EFFECTS OF
OPIUM POPPIES
• ENDOGENOUS OPIATES, E.G.
ENKEPHALIN, MODULATE THE ACTUAL
PAIN INFO CARRIED FROM THE
PERIPHERY TO THE HIGHER CENTERS
OF BRAIN
• THESE ENKEPHALIN CELLS ARE
REGULATED BY SEROTONERGIC
INNERVATION FROM RAPHE (ROLE OF
LSD, NO PAIN)
The "Gate Theory of Pain"
TOLERANCE:
-PRODUCES A NEED TO INCREASE THE
DOSE OF A DRUG IN ORDER TO
ACHIEVE THE SAME MAGNITUDE OF
EFFECT...SIGNIFICANT
CROSS-TOLERANCE TO SIMILAR
COMPOUNDS
-TOLERANCE TO OPIATES DEVELOPS
VERY RAPIDLY (I.E. A SINGLE DOSE)
ALTHOUGH NOT ALL EFFECTS
UNDERGO TOLERANCE TO THE SAME
EXTENT
TOLERANCE:
-IN GENERAL, THE EUPHORIA AND
ANALGESIA SHOW RAPID TOLERANCE,
WHILE THE CONSTIPATING EFFECTS
AND NAUSEA PERSIST EVEN AFTER
PROLONGED OPIATE USE
-TOLERANCE IS CHARACTERIZED BY A
SHORTER DURATION OF ACTION (I.E. A
METABOLIC TOLERANCE), A REDUCED
INTENSITY OF ANALGESIA AND
SEDATIVE EFFECTS, AND A
SIGNIFICANT INCREASE IN THE
AVERAGE LETHAL DOSE
-WITH SIGNIFICANT TOLERANCE OFTEN
COMES DEPENDENCE AND ADDICTION
Tolerance may be at the level
of the synapse.
-Following the activation of
second messengers genes
may be affected
-The genes trigger production
of proteins that wander back
to the pre-synaptic neuron and
tell it to stop releasing so
much dopamine
-The end effect is less
euphoria
-DEGREE OF DEPENDENCE CAN ONLY BE
MEASURED BY THE SEVERITY OF THE
WITHDRAWAL SYMPTOMS
WITHDRAWAL
-SYMPTOMS VARY IN INTENSITY DEPENDING ON
HISTORY OF DRUG USE AND THE HEALTH AND
PERSONALITY OF THE ADDICT
-SYMPTOMS ARE NOT CONSIDERED TO BE LIFE
THREATENING, ALTHOUGH THEY MAY FEEL
LIKE IT
-FLU-LIKE BEGIN AT 8-12 HR AND PEAKS AT
48-72 HOURS AFTER THE LAST DOSE.
ESSENTIAL, SYMPTOMS ARE "REBOUND" OF
SYSTEMS INITIALLY EFFECTED BY DRUG.
-SYMPTOMS- DILATED PUPILS,
LACRIMATION, WEAKNESS AND
DEPRESSION, NAUSEA AND VOMITTING,
INTESTINAL SPASMS AND DIARRHEA,
RUNNY NOSE, HOT AND COLD SWEAT
FLASHES, WEIGHT LOSS, MUSCLE
SPASMS, AND DEHYDRATION
-SYMPTOMS WILL USUALLY PERSIST FOR
7 TO 10 DAYS
-THEY WILL BE SUPPRESSED BY
ADMINISTRATION OF THE OPIATE
-SYMPTOMS WILL APPEAR IF AN
ANTAGONIST IS ADMINISTERED...EVEN
MORE SEVERE WITHDRAWAL THAN
MERE ABSTINENCE WILL CREATE
A map of the brain showing the
concentration of receptors for the brain's
own "feel good" chemicals, called
endogenous opioids
A three-dimensional view of brain areas where activations of
the endogenous opioid receptors during sustained pain were
associated with reductions in pain affect, or the emotional
quality of the pain experience.
the dorsal portion of the anterior cingulate cortex, the thalamus
and the nucleus accumbens.
Heroin/morphine indirectly causes the increased
release of dopamine in the accumbens area
Meta-analysis of placebo acupuncture versus no acupuncture
“The analgesic effect of acupuncture is small and cannot be distinguished from bias resulting from
incomplete blinding”
Madsen, M. V. et al. BMJ 2009;338:a3115
Naturally Occurring Opiate-like Molecules
Naturally Occurring Opiate-like Molecules
IT MAY BE REWARDING TO EAT CERTAIN
FOODS BECAUSE THEY THEMSELVES
CONTAIN OPIATES
E.G. MILK (BETA-CASEOMORPHIN)
Dr. Reichelt in Norway, Dr. Cade at the University of
Florida, and others found that urine samples from people
with autism and schizophrenia contained high amounts of
the casomorphin peptide in the urine. … it has opiate
properties similar to morphine, and may plug into the same
opiate receptor sites in the brain. (from an Autism web site)
Additives, Foods, Moods and
Behaviour
The dramatic effect that
additives and foods can have on
the behaviour of our children.
“These peptides pass through the gut wall into the blood stream and
from where they deliver morphine peptides directly to the brain.
Indeed the behaviour of many autistic children is very similar to that
of a drug addict a zombie-like, disconnected state when 'high' on
their drug alternating with a frenzied, head banging, totally
uncontrollable 'cold turkey' state when they are waiting for their next
fix.”
Structure of 7-8 a.a. that is large, hydrophillic and highly
charged, Tyr-Pro-Phe-Pro-Gly-Pro-Ile
Reactions to pain were suppressed during chocolate eating
Ingestion analgesia functions to defend eating from ending. Humans become hyperphagic
when palatable food is readily available suggesting that tasty food within easy reach is
destined for defended consumption in humans as well as other animals. Humans eat more
when more food is available even when the food is stale or even when they are made
cognizant of this tendency . The biological drive to consume palatable foods to completion
outweighs opposing cognitive and motivational factors and is likely a major factor in the
recent dramatic increase in obesity in modern human societies.
Copyright ©2009 Society for Neuroscience
Foo, H. et al. J. Neurosci. 2009;29:13053-13062
Myrrh
Furanoedesma-1,3-diene (a furosesquiterpene),
from the dried resin from the bark of a shrub
(found throughout Arabia).
It is slightly more potent
than morphine and may
act via central
endogenous opiate
receptors to produce
analgesia.
May also enhance blood
clotting.
Frankincense
Fragrant resin from
Boswellia sacra tree.
May have anti-inflammatory
action similar to aspirin.
May 2008 FASEB: may be
anxiolytic and antidepressive as well.
Salvia divinorum, whose main active ingredient is the
neoclerodane diterpene Salvinorin A, is a hallucinogenic
plant in the mint family that has been used in traditional
spiritual practices for its psychoactive properties by the
Mazatecs of Oaxaca, Mexico. A potent κ opioid agonist with
no actions at the 5-HT2A serotonin receptor.