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ASAM Disclosure of
                 Relevant Financial Relationships
                       Content of Activity:
              ASAM Medical –Scientific Conference 2012

    Name       Commercial      Relevant         Relevant        No Relevant
                Interests      Financial        Financial        Financial
                             Relationships:   Relationships:   Relationships
                               What Was       For What Role      with Any
                               Received                         Commercial
                                                                 Interests
Forest Labs   Speaker Bureau $2000            Speaking fees
   c.3400 B.C. The opium poppy is cultivated in lower Mesopotamia. The Sumerians would soon

    pass along the plant to the Assyrians, from the Assyrians to the Babylonians, in turn to the

    Egyptians.

   c.1300 B.C. In the capital city of Thebes, Egyptians begin cultivation of opium thebaicum,

    grown in their famous poppy fields. The opium trade flourishes during the reign of Thutmose

    IV, Akhenaton and King Tutankhamen. The trade routes included Greece, Carthage, and

    Europe.

   c. 460 B.C. Hippocrates, "the father of medicine", dismisses the magical attributes of opium

    but acknowledges its usefulness as a narcotic and styptic in treating internal diseases,

    diseases of women and epidemics.

   330 B.C. Alexander the Great introduces opium to the people of Persia and India.

   A.D. 400 Opium thebaicum, from the Egyptian fields at Thebes, is first introduced to China by

    Arab traders.
February 2009 FDA announces
plans further to restrict access to
                                                  1903 heroin use rises
opioid-based pain-relievers
                                                  dramatically; US passes Pure
March 2009 World Health                           Food and Drug Act requiring
                                                  labels on patent medications;
Organization: 80% of the world‟s
                                                  heroin availability decreases
population lacks access to pain                                                                        1200 AD
relief. Human Rights Watch blames                                      1874 Heroin first               Opium treats
                                            1972 Snyder and            synthesized by C.               diarrhea
“over-zealous drug control                                             R. Wright
                                            Pert discover
efforts”.
                                            opiate receptor                            1600 Portuguese
                                                                                       smoke opium
                 1975 Kosterlitz and colleagues                                        1780 Persians drink
                                                                                       opium
                 isolate an endogenous opioid
                 in the brain, enkephalin
                                                                                   1803 Friedrich               400 AD
                 2003 crackdown                                                    Sertürner invents
                 on online                                                         morphine
                 pharmacies
DATA 2000

                                                 3400 BC-1300 BC opium
                                                 spreads from Mesopotamia
                                                 through Greece and Europe
 1972 Snyder and Pert discover opiate receptor



    1874 Heroin first
    synthesized by C.
    R. Wright

                1200 AD
                Opium treats
                diarrhea
   A.D. 1200 Ancient Indian medical treatises describe the use of opium for diarrhea and

    sexual debility.

   1300s Opium disappears for two hundred years from European historical record. Opium

    had become a taboo subject for those in circles of learning during the Holy Inquisition.

    In the eyes of the Inquisition, anything from the East was linked to the Devil.

   1500 The Portuguese, while trading along the East China Sea, initiate the smoking of

    opium. The effects were instantaneous as they discovered but it was a practice the

    Chinese considered barbaric and subversive.

   1527 During the height of the Reformation, opium is reintroduced into European

    medical literature by Paracelsus as laudanum.

   1600s Residents of Persia and India begin eating and drinking opium mixtures for

    recreational use.

   1601 Ships chartered by Elizabeth I are instructed to purchase the finest Indian opium

    and transport it back to England.
   1620s -1670s Opium becomes the main commodity of British trade with China.

   1680 English apothecary, Thomas Sydenham, introduces Sydenham's Laudanum, a

    compound of opium, sherry wine and herbs. His pills become popular remedies for

    numerous ailments.

   1700 The Dutch export shipments of Indian opium to China and the islands of Southeast

    Asia; the Dutch introduce the practice of smoking opium to the Chinese.

   1729 Chinese emperor, Yung Cheng, issues an edict prohibiting the smoking of opium

    and its domestic sale, except under license for use as medicine.

   1750 The British East India Company assumes control of Bengal and Bihar, opium-

    growing districts of India. British shipping dominates the opium trade out of Calcutta to

    China.

   1753 Linnaeus, the father of botany, first classifies the poppy, Papaver somniferum -

    'sleep-inducing',

   1767 The British East India Company's import of opium to China reaches a staggering two

    thousand chests of opium per year.
   1796 The import of opium into China becomes a contraband trade. Silver was smuggled

    out to pay for smuggling opium in.

   1799 China's emperor, Kia King, bans opium completely, making trade and poppy

    cultivation illegal.

   1803 Friedrich Sertürner discovers the active ingredient of opium by dissolving it in acid

    then neutralizing it with ammonia. The result: morphine.

   Physicians believe that opium had finally been perfected and tamed. Morphine is lauded

    as "God's own medicine" for its reliability, long-lasting effects and safety.

   1812 American John Cushing, under the employ of his uncles' business, James and

    Thomas H. Perkins Company of Boston, acquires his wealth from smuggling Turkish

    opium to Canton.

   1816 John Jacob Astor of New York City joins the opium smuggling trade. His American

    Fur Company purchases ten tons of Turkish opium then ships the contraband item to

    Canton on the Macedonian. Astor would later leave the China opium trade and sell solely

    to England.
   1819 Writer John Keats and other English literary personalities experiment with opium
    intended for strict recreational use - simply for the high and taken at extended, non-
    addictive intervals

   1827 E. Merck & Company of Darmstadt, Germany, begins commercial manufacturing of
    morphine.

   1830 The British dependence on opium for medicinal and recreational use reaches an all time
    high as 22,000 pounds of opium is imported from Turkey and India.

   1837 Elizabeth Barrett Browning falls under the spell of morphine. This, however, does not
    impede her ability to write "poetical paragraphs."

   March 18, 1839 Lin Tse-Hsu, imperial Chinese commissioner in charge of suppressing the
    opium traffic, orders all foreign traders to surrender their opium. In response, the British send
    expeditionary warships to the coast of China, beginning The First Opium War.

   1841 The Chinese are defeated by the British in the First Opium War. Along with paying a
    large indemnity, Hong Kong is ceded to the British.

   1843 Dr. Alexander Wood of Edinburgh discovers a new technique of administering
    morphine, injection with a syringe. He finds the effects of morphine on his patients
    instantaneous and three times more potent.
   1874 English researcher, C.R. Wright first synthesizes heroin, or diacetylmorphine, by
    boiling morphine over a stove.

   In San Francisco, smoking opium in the city limits is banned and is confined to neighboring
    Chinatowns and their opium dens.

   1890 U.S. Congress imposes a tax on opium and morphine.

   1895 Heinrich Dreser finds that diluting morphine with acetyls produces a drug without the
    common morphine side effects. Bayer begins production of diacetylmorphine and coins the
    name "heroin."

   Early 1900s The philanthropic Saint James Society in the U.S. mounts a campaign to supply
    free samples of heroin through the mail to morphine addicts who are trying give up their
    habits.

   1902 In various medical journals, physicians discuss the side effects of using heroin as a
    morphine step-down cure. Several physicians would argue that their patients suffered from
    heroin withdrawal symptoms equal to morphine addiction.

   1903 Heroin addiction rises to alarming rates.

   U.S. Congress passes the Pure Food and Drug Act requiring contents labeling on patent
    medicines by pharmaceutical companies. As a result, the availability of opiates and opiate
    consumers significantly declines.
   1948-1972 Corsican gangsters dominate the U.S. heroin market through their connection
    with Mafia drug distributors. After refining the raw Turkish opium in Marseilles
    laboratories, the heroin is made easily available for purchase on New York City streets.

   1950s U.S. efforts to contain the spread of Communism in Asia involves forging alliances
    with tribes and warlords inhabiting the areas of the Golden Triangle, (an expanse covering
    Laos, Thailand and Burma), thus providing accessibility and protection along the southeast
    border of China. In order to maintain their relationship with the warlords while continuing
    to fund the struggle against communism, the U.S. and France supply the drug warlords and
    their armies with ammunition, arms and air transport for the production and sale of opium.
    The result: an explosion in the availability and illegal flow of heroin into the United States
    and into the hands of drug dealers and addicts.

   1965-1970 U.S. involvement in Vietnam is blamed for the surge in illegal heroin being
    smuggled into the States. To aid U.S. allies, the Central Intelligence Agency (CIA) sets up a
    charter airline, Air America, to transport raw opium from Burma and Laos. As well, some of
    the opium would be transported to Marseilles by Corsican gangsters to be refined into
    heroin and shipped to the U.S via the French connection. The number of heroin addicts in
    the U.S. reaches an estimated 750,000.
   October 1970 Janis Joplin, is found dead at Hollywood's Landmark Hotel, a victim of an
    "accidental heroin overdose."

   1972 Solomon Snyder and Candace Pert discover opiate receptor in the brain.

   Mid-1970s Saigon falls. The heroin epidemic subsides. The search for a new source of raw
    opium yields Mexico's Sierra Madre. "Mexican Mud" would temporarily replace "China White"
    heroin until 1978.

   1975 Hans Kosterlitz and his colleagues isolate and purify an endogenous opioid in the brain,
    enkephalin

   1978 The U.S. and Mexican governments find a means to eliminate the source of raw opium - by
    spraying poppy fields with Agent Orange. In response, another source of heroin is found in the
    Golden Crescent area - Iran, Afghanistan and Pakistan, creating a dramatic upsurge in the
    production and trade of illegal heroin.

   1982 Comedian John Belushi of Animal House fame, dies of a heroin-cocaine - "speedball"
    overdose.

   1992 Colombia's drug lords are said to be introducing a high-grade form of heroin into the
    United States.

   1993 The Thai army with support from the U.S. Drug Enforcement Agency (DEA) launches its
    operation to destroy thousands of acres of opium poppies from the fields of the Golden Triangle
    region.
   January 1994 Efforts to eradicate opium at its source remains unsuccessful. The Clinton
    Administration orders a shift in policy away from the anti- drug campaigns of previous
    administrations. Instead the focus includes "institution building" with the hope that by
    "strengthening democratic governments abroad, [it] will foster law-abiding behavior and promote
    legitimate economic opportunity."

   1995 The Golden Triangle region of Southeast Asia is now the leader in opium production,
    yielding 2,500 tons annually. According to U.S. drug experts, there are new drug trafficking
    routes from Burma through Laos, to southern China, Cambodia and Vietnam.

   November 1996 International drug trafficking organizations, including China, Nigeria, Colombia
    and Mexico are said to be "aggressively marketing heroin in the United States and Europe."

   1999 Bumper opium crop of 4,600 tons in Afghanistan. UN Drug Control Program estimates
    around 75% of world's heroin production is of Afghan origin.

   2000 Taliban leader Mullah Omar bans poppy cultivation in Afghanistan; United Nations Drug
    Control Program confirms opium production eradicated.

   Autumn 2001 War in Afghanistan; heroin floods the Pakistan market. Taliban regime
    overthrown.
   October 2002 U.N. Drug Control and Crime Prevention Agency announces Afghanistan has
    regained its position as the world's largest opium producer.

   December 2002 UK Government health plan will make heroin available free on National
    Health Service "to all those with a clinical need for it". Consumers are skeptical.

   October 2003 US Food and Drug Administration (FDA) and Drug Enforcement
    Administration (DEA) launch special task force to curb surge in Net-based sales of narcotics
    from online pharmacies.

   January 2004 Consumer groups file a lawsuit against Oxycontin maker Purdue Pharma. The
    company is alleged to have used fraudulent patents and deceptive trade practices.

   September 2004 A Tasmanian company publishes details of its genetically-engineered
    opium poppies. mutants do not produce morphine or codeine. Tasmania is the source of
    some 40% of the world's legal opiates; its native crop of poppies is already being re-
    engineered with the mutant stain. Conversely, some investigators expect that the
    development of genetically-engineered plants and microorganisms to manufacture potent
    psychoactive compounds will become widespread later in the 21st century. Research into
    transgenic psychotropic botanicals and microbes is controversial; genes from mutants have
    a habit of spreading into the wild population by accident as well as design.
   October 2004 Unannounced withdrawal of newly-issued DEA guidelines to pain
    specialists. The guidelines had pledged that physicians wouldn't be arrested for
    providing adequate pain-relief to their patients. DEA drug-diversion chief Patricia Good
    earlier stated that the new rules were meant to eliminate an "aura of fear" that stopped
    doctors treating pain aggressively.

   December 2004 McLean pain-treatment specialist Dr William E. Hurwitz is sent to prison
    for allegedly "excessive" prescription of opioid painkillers to chronic pain patients.
    Testifying in court, Dr Hurwitz describes the abrupt stoppage of prescriptions as
    "tantamount to torture".

   May 2005 Researchers at Ernest Gallo Clinic and Research Center in Emeryville,
    California, inhibit expression of the AGS3 gene in the core of nucleus accumbens.
    Experimentally blocking the AGS3 gene curbs the desire for heroin in addicted rodents.
    By contrast, activation of the reward centers of the nucleus accumbens is immensely
    pleasurable and addictive. The possible effects of overexpression and gene amplification
    of AGS3 remain unexplored.
    May 2006 In Mexico, Congress passes a bill legalizing the private personal use of all
     drugs, including opium and all opiate-based drugs. President Vicente Fox promises to to
     sign the measure, but buckles a day later under US government pressure. The bill is
     referred back to Congress for changes.

    September 2006The head of the United Nations Office on Drugs and Crime reports that
     Afghanistan's harvest in 2006 will be around 6,100 metric tons of opium - a world
     record. This figure amounts to some 92% of global opium supply.

1.    November 2006 S enior UK police officer Howard Roberts advocates legalization of
      heroin and its availability without charge on National Health Service (NHS) prescription.

    August 2007 Afghanistan's poppy production rises an estimated 15 percent over 2006.
     Afghanistan now accounts for 95 percent of the world's opium poppy crop, a 3
     percentage point increase over last year. The US State Department's top counternarcotics
     official Tom Schweich claims that Afghanistan is now "providing close to 95 percent of
     the world's heroin".

    November 2008 Swiss voters overwhelmingly endorse a permanent and comprehensive
     legalized heroin program.
   February 2009 FDA announces plans further to restrict access to opioid-based pain-
    relievers by American citizens and their doctors.

   March 2009 According to the World Health Organization, around 80% of the world‟s
    population does not have adequate access to pain relief. The international organization
    Human Rights Watch blames a failure of leadership, inadequate training of health care
    workers, and “over-zealous drug control efforts”.

   July 2011 Seattle hosts Kappa Therapeutics, dedicated to kappa opioids and
    antagonists. Investigators hope that selective kappa opioid antagonists can be used to
    treat anxiety disorders, clinical depression, anhedonia, eating disorders, alcoholism and
    a variety of substance abuse disorders.
Opioid analgesia is limited by tolerance.
Physical dependence eliminates free use of opioids
Opioids cause euphoria, which removes insight, fueling addiction.

Respiratory depression from illicit opioid use is a rapidly-growing
cause of death.
Many patients cannot control their own use of opioids
Divisions within the medical community debate the utility of
opioid use for chronic pain.
Motivations of pharmaceutical companies are questions
   Growing number of patients taking buprenorphine for
    treatment of opioid dependence.
   During need for analgesia e.g. trauma or surgery,
    recommendations call for lowering dose of buprenorphine
    and treating pain using high dosages of opioid agonists, with
    careful monitoring of respiratory function.
   Patients maintained on buprenorphine were given mu opioids for pain
    control. Patients included those with acute surgical pain, e.g. total knee
    replacement, cholecystectomy, median sternotomy, hysterectomy, and
    sinus surgery.



   Patients on buprenorphine undergoing surgery experienced adequate to
    good analgesia using oxycodone, 15-30 mg every 4 hours, without
    subjective euphoria. Patients on PCA, or taking agonists at home,
    described being able to control dosing of the agonist, despite inability to
    control mu opioid use when not on buprenorphine.
   Clue– „precipitated withdrawal.‟
    If a person has a high opioid
    tolerance, > 100 mg
    oxycodone per day, induction
    with buprenorphine will cause
    precipitated withdrawal. The
    buprenorphine „pulls‟ tolerance
    down to the maximum effect of
    the partial agonist, causing
    withdrawal as tolerance resets
    at that level.
   If surgical-maintained patient is KEPT on
    buprenorphine, and given 100-200 mg of
    oxycodone per day, the patient experiences NO
    withdrawal, provided the buprenorphine is not
    discontinued.
   Analgesia DOES occur.
   Patient 1: 34-y-o Caucasian woman, history of patient foramen
    ovale. Trans-venous patch eventually eroded through heart
    causing tamponade, open repair complicated by sternal
    dehiscence, months in ICU. Discharged eventually on 400 mg of
    oxycodone per day. Dose increased for worsening pain in ribs
    and sternum; dosed to 600 mg oxycodone per day, then doctor
    decided he „was not comfortable with case anymore.‟ Started on
    buprenorphine/Suboxone; required months of detox off high-
    dose oxycodone.
   Initially did well on buprenorphine, but titanium device fractured
    and sternum opened, requiring new titanium implant to be
    inserted. Maintained on low dose of buprenorphine (4 mg);
    oxycodone added.
   After new implant patient wanted to try buprenorphine for
    pain control. EASILY stopped oxycodone; buprenorphine
    increased to 16 mg per day. Initially had relief, but relief
    dissipated with tolerance. Reduced buprenorphine from 8 mg
    to 4 mg per day, and given 15 mg oxycodone every 4 hours.
    Eventually changed to Oxycontin 20 mg TID plus
    buprenorphine 4 mg; uses up to 5 mg oxycodone PRN.
    Stable on dose for over 2 years; reports „best pain relief in
    years; takes own meds and controls them; reports pain relief
    but no warmth or euphoria.
   Patient very happy with outcome.
   Patient 2: 22-y-o Caucasian woman developed advanced
    scoliosis, had thoraco-lumbar fusion at age 18. Several years
    later, repair came apart; surgeon would not help. Has
    radicular compression at multiple levels. Using over 600 mg
    oxycodone per day, supplementing with IV heroin.
   Difficult detox over several months to dose of oxycodone
    approximately equal to 100 mg per day, then induced to
    buprenorphine. Significant withdrawal precipitated.
   Patient started on buprenorphine 4 mg per day, plus
    oxycodone 15 mg every 4 hours. Case complicated when
    patient‟s „using‟ bf returned onto scene; attempted to keep
    medications with patient‟s mother.
   Patient appeared to be doing well; was working, for example
    but always complaining of need for greater relief. At two
    month follow-up, urine did not contain buprenorphine;
    patient reported that she felt better without the
    buprenorphine. We attempted to manage her pain, but her
    tolerance rose very quickly, back to the 400-600 mg of
    oxycodone per day that she was using before.
   She was discharged from our practice for violating terms of
    treatment. At that point, she begged to come back, and to
    stay on buprenorphine; she insisted that it worked well for
    her and she „couldn‟t explain‟ why she stopped the
    buprenorphine. She was referred to a different physician.
   Patient 3: 24-y-o HS baseball star. Tore rotator cuff in
    dominant arm. Arm pulled traumatically from socket on three
    occasions. After repair, lidocaine infused into joint for pain
    relief; destroyed all cartilage in joint ($ settlement by company).
    Chronic, severe „bone on bone‟ pain in dominant arm; also
    brachial plexus compression from scar tissue from repeated
    surgeries. Using oxycodone, 200 – 400 mg/day.
   Lost his physician for testing positive for marijuana. Offered to
    try combined technique. Detoxed over several months, then
    started on buprenorphine, 16 mg per day. Pain relief initially
    helpful; dissipated over several months, assumedly from
    tolerance.
   Buprenorphine dose lowed to 4 mg per day, and oxycodone
    added– 7.5-15 mg oxycodone every 4 hours as needed.
    Patient reports excellent pain relief at 2 years. No dose
    escalation. Reports „odd analgesia‟ without any euphoric
    component of opioids.
   Also has been able to move forward academically and in
    workforce. Controls his own medications– something that he
    continues to be surprised by. Anticipates using similar
    combination for extended period of time.
   Patient 4: 50-y-o executive, Crohn‟s disease for 20 years; allergic
    to biological therapies. Multiple surgeries and adhesions. On
    buprenorphine, but continues to have severe pain. Was taking
    buprenorphine from a different physician. For an acute
    procedure, we lowed buprenorphine from 8 to 4 mg per dad, and
    had him use oxycodone for post-op pain. He appreciated the
    pain relief to the point that he asked to stay on combination.
    Now takes buprenorphine 4 mg, plus Oxycontin 20 mg TID and
    oxycodone 15 mg every 4 hours as needed, total of 110 mg
    oxycodone per day. Believes that his pain relief is better than in
    past, and has same reaction– no euphoria, and no desire to take
    more than what is needed for pain.
   Patient 5: 42-y-o Caucasian man, tore spinal nerves from cord
    during snowmobiling injury. Severe phantom limb pain with
    spasms in dominant arm. Taking over 500 mg oxycodone per
    day before discharged by his doctor, who was „no longer
    comfortable‟ prescribing a high dose of opioid. Patient self-
    detoxed (very ill), and started by us on buprenorphine 16 mg
    per day. Good pain relief for several months, then overcome
    by worsening pain „spasms‟. Neurosurgeon placed intracranial
    stimulator that would precipitate seizures when turned up– but
    no pain relief. We added oxycodone 15 mg every 4 hours, and
    2400 mg of gabapentin per day.
   Gabapentin reduced „spasms‟ dramatically, and oxycodone
    largely removed aching and phantom pains. Patient happy
    with combination, and as with others, finds less euphoria, but
    also less sedation and less cravings, using the combinations
    than when using oxycodone alone.
   Stable analgesia without dose escalation for past 18 months.
   Patients report that pain is relieved, but they are
    disappointed by lack of „opioid feeling.‟
   They are surprised that they can make a script last
    „on time‟ for entire month.
   Tolerance does not appear to occur, out for 24
    months in one patient and 18 months in another.
   Dose escalation was easily prevented in all patients
   Place patients on dose of buprenorphine sufficient to benefit
    from „ceiling effect‟ of buprenorphine– to obtain craving
    reduction.
   Use lowest possible dose of buprenorphine, to avoid blocking
    effects of agonists, but that still provides constant opioid
    effect to brain receptors.
   Add potent opioid agonist (oxycodone) and assess pain relief,
    adjusting agonist dosage to find proper level and then
    attempt to make few changes in dose going forward.
Combination opioid treatment with buprenorphine (4 mg per
day) and mu agonists (oxycodone 15-30 mg every 4 hours)
resulted in adequate analgesia. This analgesia was maintained
for up to 24 months without need for dose escalation. Patients
reported the absence of euphoria, and were in most cases to
manage their own prescriptions-- something not possible in
the absence of buprenorphine.*


*Patient two discontinued buprenorphine without permission,
and shortly afterward ran out of oxycodone early.
   If buprenorphine is stopped, the addictiveness of
    the opioid agonist returns.
   Dose escalation returns rapidly, and tolerance
    appears to develop rapidly as well.
   Only way to restart combination is to STOP agonist
    first, then induce with buprenorphine. Restarting
    buprenorphine will otherwise precipitate
    withdrawal.
All patients taking the combination of buprenorphine and
oxycodone described a 'different feeling' to the oxycodone
compared to their experience before buprenorphine. They reported
that while the oxycodone removed their pain, there was no sense of
euphoria from the oxycodone.


Tolerance/dose escalation has always been the major barrier to
long-term opioid analgesia. The partial agonist buprenorphine
appeared to anchor tolerance to the '40 mg methadone' level known
to be the comparative potency of buprenorphine, allowing for long-
term analgesic effects from mu opioid agonists.
Preliminary investigations suggests that other potent mu agonists
would be appropriate candidates for combination analgesia. For
example, a dual patch method with fentanyl and buprenorphine.
The effects of buprenorphine in mitigating euphoria suggest a role in
affecting the current epidemic of opioid dependence. In other words,
imagine if every opioid agonist was intrinsically attached to
buprenorphine! Opioid dependence is currently at epidemic levels, and
any means to reduce diversion of opioids will save lives. Combining
buprenorphine or other partial agonists with agonists may be one
answer to the opioid dependence problem. Such combinations may
also reduce the risk of addiction for individual patients who are
exposed to potent opioids after surgery.
   Good evidence that true pain is present
   Stable on buprenorphine for at minimum several
    months
   Evidence for motivation to avoid old life-style, i.e.
    sick and tired.
   Trustworthy, non-using partner to witness/control
    medications
Opioid analgesia is limited by tolerance, addiction and respiratory
depression. Buprenorphine, when combined with a mu agonist, causes a
range of effects. Patients experience dose-related analgesia from the
agonist without euphoria. Patients unable to control their use of a mu
agonist alone gain that control when on buprenorphine. And
buprenorphine appears to anchor tolerance, maintaining analgesia without
dose escalation. This finding offers huge implications for pain
management.
                   Jeffrey T Junig MD PhD
                     Fond du Lac Psychiatry
                     Asst. Clinical Professor of Psychiatry
                     Medical College of Wisconsin

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  • 1.
  • 2. ASAM Disclosure of Relevant Financial Relationships Content of Activity: ASAM Medical –Scientific Conference 2012 Name Commercial Relevant Relevant No Relevant Interests Financial Financial Financial Relationships: Relationships: Relationships What Was For What Role with Any Received Commercial Interests Forest Labs Speaker Bureau $2000 Speaking fees
  • 3. c.3400 B.C. The opium poppy is cultivated in lower Mesopotamia. The Sumerians would soon pass along the plant to the Assyrians, from the Assyrians to the Babylonians, in turn to the Egyptians.  c.1300 B.C. In the capital city of Thebes, Egyptians begin cultivation of opium thebaicum, grown in their famous poppy fields. The opium trade flourishes during the reign of Thutmose IV, Akhenaton and King Tutankhamen. The trade routes included Greece, Carthage, and Europe.  c. 460 B.C. Hippocrates, "the father of medicine", dismisses the magical attributes of opium but acknowledges its usefulness as a narcotic and styptic in treating internal diseases, diseases of women and epidemics.  330 B.C. Alexander the Great introduces opium to the people of Persia and India.  A.D. 400 Opium thebaicum, from the Egyptian fields at Thebes, is first introduced to China by Arab traders.
  • 4. February 2009 FDA announces plans further to restrict access to 1903 heroin use rises opioid-based pain-relievers dramatically; US passes Pure March 2009 World Health Food and Drug Act requiring labels on patent medications; Organization: 80% of the world‟s heroin availability decreases population lacks access to pain 1200 AD relief. Human Rights Watch blames 1874 Heroin first Opium treats 1972 Snyder and synthesized by C. diarrhea “over-zealous drug control R. Wright Pert discover efforts”. opiate receptor 1600 Portuguese smoke opium 1975 Kosterlitz and colleagues 1780 Persians drink opium isolate an endogenous opioid in the brain, enkephalin 1803 Friedrich 400 AD 2003 crackdown Sertürner invents on online morphine pharmacies
  • 5. DATA 2000 3400 BC-1300 BC opium spreads from Mesopotamia through Greece and Europe 1972 Snyder and Pert discover opiate receptor 1874 Heroin first synthesized by C. R. Wright 1200 AD Opium treats diarrhea
  • 6. A.D. 1200 Ancient Indian medical treatises describe the use of opium for diarrhea and sexual debility.  1300s Opium disappears for two hundred years from European historical record. Opium had become a taboo subject for those in circles of learning during the Holy Inquisition. In the eyes of the Inquisition, anything from the East was linked to the Devil.  1500 The Portuguese, while trading along the East China Sea, initiate the smoking of opium. The effects were instantaneous as they discovered but it was a practice the Chinese considered barbaric and subversive.  1527 During the height of the Reformation, opium is reintroduced into European medical literature by Paracelsus as laudanum.  1600s Residents of Persia and India begin eating and drinking opium mixtures for recreational use.  1601 Ships chartered by Elizabeth I are instructed to purchase the finest Indian opium and transport it back to England.
  • 7. 1620s -1670s Opium becomes the main commodity of British trade with China.  1680 English apothecary, Thomas Sydenham, introduces Sydenham's Laudanum, a compound of opium, sherry wine and herbs. His pills become popular remedies for numerous ailments.  1700 The Dutch export shipments of Indian opium to China and the islands of Southeast Asia; the Dutch introduce the practice of smoking opium to the Chinese.  1729 Chinese emperor, Yung Cheng, issues an edict prohibiting the smoking of opium and its domestic sale, except under license for use as medicine.  1750 The British East India Company assumes control of Bengal and Bihar, opium- growing districts of India. British shipping dominates the opium trade out of Calcutta to China.  1753 Linnaeus, the father of botany, first classifies the poppy, Papaver somniferum - 'sleep-inducing',  1767 The British East India Company's import of opium to China reaches a staggering two thousand chests of opium per year.
  • 8. 1796 The import of opium into China becomes a contraband trade. Silver was smuggled out to pay for smuggling opium in.  1799 China's emperor, Kia King, bans opium completely, making trade and poppy cultivation illegal.  1803 Friedrich Sertürner discovers the active ingredient of opium by dissolving it in acid then neutralizing it with ammonia. The result: morphine.  Physicians believe that opium had finally been perfected and tamed. Morphine is lauded as "God's own medicine" for its reliability, long-lasting effects and safety.  1812 American John Cushing, under the employ of his uncles' business, James and Thomas H. Perkins Company of Boston, acquires his wealth from smuggling Turkish opium to Canton.  1816 John Jacob Astor of New York City joins the opium smuggling trade. His American Fur Company purchases ten tons of Turkish opium then ships the contraband item to Canton on the Macedonian. Astor would later leave the China opium trade and sell solely to England.
  • 9. 1819 Writer John Keats and other English literary personalities experiment with opium intended for strict recreational use - simply for the high and taken at extended, non- addictive intervals  1827 E. Merck & Company of Darmstadt, Germany, begins commercial manufacturing of morphine.  1830 The British dependence on opium for medicinal and recreational use reaches an all time high as 22,000 pounds of opium is imported from Turkey and India.  1837 Elizabeth Barrett Browning falls under the spell of morphine. This, however, does not impede her ability to write "poetical paragraphs."  March 18, 1839 Lin Tse-Hsu, imperial Chinese commissioner in charge of suppressing the opium traffic, orders all foreign traders to surrender their opium. In response, the British send expeditionary warships to the coast of China, beginning The First Opium War.  1841 The Chinese are defeated by the British in the First Opium War. Along with paying a large indemnity, Hong Kong is ceded to the British.  1843 Dr. Alexander Wood of Edinburgh discovers a new technique of administering morphine, injection with a syringe. He finds the effects of morphine on his patients instantaneous and three times more potent.
  • 10. 1874 English researcher, C.R. Wright first synthesizes heroin, or diacetylmorphine, by boiling morphine over a stove.  In San Francisco, smoking opium in the city limits is banned and is confined to neighboring Chinatowns and their opium dens.  1890 U.S. Congress imposes a tax on opium and morphine.  1895 Heinrich Dreser finds that diluting morphine with acetyls produces a drug without the common morphine side effects. Bayer begins production of diacetylmorphine and coins the name "heroin."  Early 1900s The philanthropic Saint James Society in the U.S. mounts a campaign to supply free samples of heroin through the mail to morphine addicts who are trying give up their habits.  1902 In various medical journals, physicians discuss the side effects of using heroin as a morphine step-down cure. Several physicians would argue that their patients suffered from heroin withdrawal symptoms equal to morphine addiction.  1903 Heroin addiction rises to alarming rates.  U.S. Congress passes the Pure Food and Drug Act requiring contents labeling on patent medicines by pharmaceutical companies. As a result, the availability of opiates and opiate consumers significantly declines.
  • 11. 1948-1972 Corsican gangsters dominate the U.S. heroin market through their connection with Mafia drug distributors. After refining the raw Turkish opium in Marseilles laboratories, the heroin is made easily available for purchase on New York City streets.  1950s U.S. efforts to contain the spread of Communism in Asia involves forging alliances with tribes and warlords inhabiting the areas of the Golden Triangle, (an expanse covering Laos, Thailand and Burma), thus providing accessibility and protection along the southeast border of China. In order to maintain their relationship with the warlords while continuing to fund the struggle against communism, the U.S. and France supply the drug warlords and their armies with ammunition, arms and air transport for the production and sale of opium. The result: an explosion in the availability and illegal flow of heroin into the United States and into the hands of drug dealers and addicts.  1965-1970 U.S. involvement in Vietnam is blamed for the surge in illegal heroin being smuggled into the States. To aid U.S. allies, the Central Intelligence Agency (CIA) sets up a charter airline, Air America, to transport raw opium from Burma and Laos. As well, some of the opium would be transported to Marseilles by Corsican gangsters to be refined into heroin and shipped to the U.S via the French connection. The number of heroin addicts in the U.S. reaches an estimated 750,000.
  • 12. October 1970 Janis Joplin, is found dead at Hollywood's Landmark Hotel, a victim of an "accidental heroin overdose."  1972 Solomon Snyder and Candace Pert discover opiate receptor in the brain.  Mid-1970s Saigon falls. The heroin epidemic subsides. The search for a new source of raw opium yields Mexico's Sierra Madre. "Mexican Mud" would temporarily replace "China White" heroin until 1978.  1975 Hans Kosterlitz and his colleagues isolate and purify an endogenous opioid in the brain, enkephalin  1978 The U.S. and Mexican governments find a means to eliminate the source of raw opium - by spraying poppy fields with Agent Orange. In response, another source of heroin is found in the Golden Crescent area - Iran, Afghanistan and Pakistan, creating a dramatic upsurge in the production and trade of illegal heroin.  1982 Comedian John Belushi of Animal House fame, dies of a heroin-cocaine - "speedball" overdose.  1992 Colombia's drug lords are said to be introducing a high-grade form of heroin into the United States.  1993 The Thai army with support from the U.S. Drug Enforcement Agency (DEA) launches its operation to destroy thousands of acres of opium poppies from the fields of the Golden Triangle region.
  • 13. January 1994 Efforts to eradicate opium at its source remains unsuccessful. The Clinton Administration orders a shift in policy away from the anti- drug campaigns of previous administrations. Instead the focus includes "institution building" with the hope that by "strengthening democratic governments abroad, [it] will foster law-abiding behavior and promote legitimate economic opportunity."  1995 The Golden Triangle region of Southeast Asia is now the leader in opium production, yielding 2,500 tons annually. According to U.S. drug experts, there are new drug trafficking routes from Burma through Laos, to southern China, Cambodia and Vietnam.  November 1996 International drug trafficking organizations, including China, Nigeria, Colombia and Mexico are said to be "aggressively marketing heroin in the United States and Europe."  1999 Bumper opium crop of 4,600 tons in Afghanistan. UN Drug Control Program estimates around 75% of world's heroin production is of Afghan origin.  2000 Taliban leader Mullah Omar bans poppy cultivation in Afghanistan; United Nations Drug Control Program confirms opium production eradicated.  Autumn 2001 War in Afghanistan; heroin floods the Pakistan market. Taliban regime overthrown.
  • 14. October 2002 U.N. Drug Control and Crime Prevention Agency announces Afghanistan has regained its position as the world's largest opium producer.  December 2002 UK Government health plan will make heroin available free on National Health Service "to all those with a clinical need for it". Consumers are skeptical.  October 2003 US Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) launch special task force to curb surge in Net-based sales of narcotics from online pharmacies.  January 2004 Consumer groups file a lawsuit against Oxycontin maker Purdue Pharma. The company is alleged to have used fraudulent patents and deceptive trade practices.  September 2004 A Tasmanian company publishes details of its genetically-engineered opium poppies. mutants do not produce morphine or codeine. Tasmania is the source of some 40% of the world's legal opiates; its native crop of poppies is already being re- engineered with the mutant stain. Conversely, some investigators expect that the development of genetically-engineered plants and microorganisms to manufacture potent psychoactive compounds will become widespread later in the 21st century. Research into transgenic psychotropic botanicals and microbes is controversial; genes from mutants have a habit of spreading into the wild population by accident as well as design.
  • 15. October 2004 Unannounced withdrawal of newly-issued DEA guidelines to pain specialists. The guidelines had pledged that physicians wouldn't be arrested for providing adequate pain-relief to their patients. DEA drug-diversion chief Patricia Good earlier stated that the new rules were meant to eliminate an "aura of fear" that stopped doctors treating pain aggressively.  December 2004 McLean pain-treatment specialist Dr William E. Hurwitz is sent to prison for allegedly "excessive" prescription of opioid painkillers to chronic pain patients. Testifying in court, Dr Hurwitz describes the abrupt stoppage of prescriptions as "tantamount to torture".  May 2005 Researchers at Ernest Gallo Clinic and Research Center in Emeryville, California, inhibit expression of the AGS3 gene in the core of nucleus accumbens. Experimentally blocking the AGS3 gene curbs the desire for heroin in addicted rodents. By contrast, activation of the reward centers of the nucleus accumbens is immensely pleasurable and addictive. The possible effects of overexpression and gene amplification of AGS3 remain unexplored.
  • 16. May 2006 In Mexico, Congress passes a bill legalizing the private personal use of all drugs, including opium and all opiate-based drugs. President Vicente Fox promises to to sign the measure, but buckles a day later under US government pressure. The bill is referred back to Congress for changes.  September 2006The head of the United Nations Office on Drugs and Crime reports that Afghanistan's harvest in 2006 will be around 6,100 metric tons of opium - a world record. This figure amounts to some 92% of global opium supply. 1. November 2006 S enior UK police officer Howard Roberts advocates legalization of heroin and its availability without charge on National Health Service (NHS) prescription.  August 2007 Afghanistan's poppy production rises an estimated 15 percent over 2006. Afghanistan now accounts for 95 percent of the world's opium poppy crop, a 3 percentage point increase over last year. The US State Department's top counternarcotics official Tom Schweich claims that Afghanistan is now "providing close to 95 percent of the world's heroin".  November 2008 Swiss voters overwhelmingly endorse a permanent and comprehensive legalized heroin program.
  • 17. February 2009 FDA announces plans further to restrict access to opioid-based pain- relievers by American citizens and their doctors.  March 2009 According to the World Health Organization, around 80% of the world‟s population does not have adequate access to pain relief. The international organization Human Rights Watch blames a failure of leadership, inadequate training of health care workers, and “over-zealous drug control efforts”.  July 2011 Seattle hosts Kappa Therapeutics, dedicated to kappa opioids and antagonists. Investigators hope that selective kappa opioid antagonists can be used to treat anxiety disorders, clinical depression, anhedonia, eating disorders, alcoholism and a variety of substance abuse disorders.
  • 18.
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  • 20. Opioid analgesia is limited by tolerance. Physical dependence eliminates free use of opioids Opioids cause euphoria, which removes insight, fueling addiction. Respiratory depression from illicit opioid use is a rapidly-growing cause of death. Many patients cannot control their own use of opioids Divisions within the medical community debate the utility of opioid use for chronic pain. Motivations of pharmaceutical companies are questions
  • 21. Growing number of patients taking buprenorphine for treatment of opioid dependence.  During need for analgesia e.g. trauma or surgery, recommendations call for lowering dose of buprenorphine and treating pain using high dosages of opioid agonists, with careful monitoring of respiratory function.
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  • 24.
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  • 26. Patients maintained on buprenorphine were given mu opioids for pain control. Patients included those with acute surgical pain, e.g. total knee replacement, cholecystectomy, median sternotomy, hysterectomy, and sinus surgery.  Patients on buprenorphine undergoing surgery experienced adequate to good analgesia using oxycodone, 15-30 mg every 4 hours, without subjective euphoria. Patients on PCA, or taking agonists at home, described being able to control dosing of the agonist, despite inability to control mu opioid use when not on buprenorphine.
  • 27. Clue– „precipitated withdrawal.‟ If a person has a high opioid tolerance, > 100 mg oxycodone per day, induction with buprenorphine will cause precipitated withdrawal. The buprenorphine „pulls‟ tolerance down to the maximum effect of the partial agonist, causing withdrawal as tolerance resets at that level.
  • 28. If surgical-maintained patient is KEPT on buprenorphine, and given 100-200 mg of oxycodone per day, the patient experiences NO withdrawal, provided the buprenorphine is not discontinued.  Analgesia DOES occur.
  • 29. Patient 1: 34-y-o Caucasian woman, history of patient foramen ovale. Trans-venous patch eventually eroded through heart causing tamponade, open repair complicated by sternal dehiscence, months in ICU. Discharged eventually on 400 mg of oxycodone per day. Dose increased for worsening pain in ribs and sternum; dosed to 600 mg oxycodone per day, then doctor decided he „was not comfortable with case anymore.‟ Started on buprenorphine/Suboxone; required months of detox off high- dose oxycodone.  Initially did well on buprenorphine, but titanium device fractured and sternum opened, requiring new titanium implant to be inserted. Maintained on low dose of buprenorphine (4 mg); oxycodone added.
  • 30. After new implant patient wanted to try buprenorphine for pain control. EASILY stopped oxycodone; buprenorphine increased to 16 mg per day. Initially had relief, but relief dissipated with tolerance. Reduced buprenorphine from 8 mg to 4 mg per day, and given 15 mg oxycodone every 4 hours. Eventually changed to Oxycontin 20 mg TID plus buprenorphine 4 mg; uses up to 5 mg oxycodone PRN. Stable on dose for over 2 years; reports „best pain relief in years; takes own meds and controls them; reports pain relief but no warmth or euphoria.  Patient very happy with outcome.
  • 31. Patient 2: 22-y-o Caucasian woman developed advanced scoliosis, had thoraco-lumbar fusion at age 18. Several years later, repair came apart; surgeon would not help. Has radicular compression at multiple levels. Using over 600 mg oxycodone per day, supplementing with IV heroin.  Difficult detox over several months to dose of oxycodone approximately equal to 100 mg per day, then induced to buprenorphine. Significant withdrawal precipitated.  Patient started on buprenorphine 4 mg per day, plus oxycodone 15 mg every 4 hours. Case complicated when patient‟s „using‟ bf returned onto scene; attempted to keep medications with patient‟s mother.
  • 32. Patient appeared to be doing well; was working, for example but always complaining of need for greater relief. At two month follow-up, urine did not contain buprenorphine; patient reported that she felt better without the buprenorphine. We attempted to manage her pain, but her tolerance rose very quickly, back to the 400-600 mg of oxycodone per day that she was using before.  She was discharged from our practice for violating terms of treatment. At that point, she begged to come back, and to stay on buprenorphine; she insisted that it worked well for her and she „couldn‟t explain‟ why she stopped the buprenorphine. She was referred to a different physician.
  • 33. Patient 3: 24-y-o HS baseball star. Tore rotator cuff in dominant arm. Arm pulled traumatically from socket on three occasions. After repair, lidocaine infused into joint for pain relief; destroyed all cartilage in joint ($ settlement by company). Chronic, severe „bone on bone‟ pain in dominant arm; also brachial plexus compression from scar tissue from repeated surgeries. Using oxycodone, 200 – 400 mg/day.  Lost his physician for testing positive for marijuana. Offered to try combined technique. Detoxed over several months, then started on buprenorphine, 16 mg per day. Pain relief initially helpful; dissipated over several months, assumedly from tolerance.
  • 34. Buprenorphine dose lowed to 4 mg per day, and oxycodone added– 7.5-15 mg oxycodone every 4 hours as needed. Patient reports excellent pain relief at 2 years. No dose escalation. Reports „odd analgesia‟ without any euphoric component of opioids.  Also has been able to move forward academically and in workforce. Controls his own medications– something that he continues to be surprised by. Anticipates using similar combination for extended period of time.
  • 35. Patient 4: 50-y-o executive, Crohn‟s disease for 20 years; allergic to biological therapies. Multiple surgeries and adhesions. On buprenorphine, but continues to have severe pain. Was taking buprenorphine from a different physician. For an acute procedure, we lowed buprenorphine from 8 to 4 mg per dad, and had him use oxycodone for post-op pain. He appreciated the pain relief to the point that he asked to stay on combination. Now takes buprenorphine 4 mg, plus Oxycontin 20 mg TID and oxycodone 15 mg every 4 hours as needed, total of 110 mg oxycodone per day. Believes that his pain relief is better than in past, and has same reaction– no euphoria, and no desire to take more than what is needed for pain.
  • 36. Patient 5: 42-y-o Caucasian man, tore spinal nerves from cord during snowmobiling injury. Severe phantom limb pain with spasms in dominant arm. Taking over 500 mg oxycodone per day before discharged by his doctor, who was „no longer comfortable‟ prescribing a high dose of opioid. Patient self- detoxed (very ill), and started by us on buprenorphine 16 mg per day. Good pain relief for several months, then overcome by worsening pain „spasms‟. Neurosurgeon placed intracranial stimulator that would precipitate seizures when turned up– but no pain relief. We added oxycodone 15 mg every 4 hours, and 2400 mg of gabapentin per day.
  • 37. Gabapentin reduced „spasms‟ dramatically, and oxycodone largely removed aching and phantom pains. Patient happy with combination, and as with others, finds less euphoria, but also less sedation and less cravings, using the combinations than when using oxycodone alone.  Stable analgesia without dose escalation for past 18 months.
  • 38. Patients report that pain is relieved, but they are disappointed by lack of „opioid feeling.‟  They are surprised that they can make a script last „on time‟ for entire month.  Tolerance does not appear to occur, out for 24 months in one patient and 18 months in another.  Dose escalation was easily prevented in all patients
  • 39. Place patients on dose of buprenorphine sufficient to benefit from „ceiling effect‟ of buprenorphine– to obtain craving reduction.  Use lowest possible dose of buprenorphine, to avoid blocking effects of agonists, but that still provides constant opioid effect to brain receptors.  Add potent opioid agonist (oxycodone) and assess pain relief, adjusting agonist dosage to find proper level and then attempt to make few changes in dose going forward.
  • 40.
  • 41. Combination opioid treatment with buprenorphine (4 mg per day) and mu agonists (oxycodone 15-30 mg every 4 hours) resulted in adequate analgesia. This analgesia was maintained for up to 24 months without need for dose escalation. Patients reported the absence of euphoria, and were in most cases to manage their own prescriptions-- something not possible in the absence of buprenorphine.* *Patient two discontinued buprenorphine without permission, and shortly afterward ran out of oxycodone early.
  • 42. If buprenorphine is stopped, the addictiveness of the opioid agonist returns.  Dose escalation returns rapidly, and tolerance appears to develop rapidly as well.  Only way to restart combination is to STOP agonist first, then induce with buprenorphine. Restarting buprenorphine will otherwise precipitate withdrawal.
  • 43. All patients taking the combination of buprenorphine and oxycodone described a 'different feeling' to the oxycodone compared to their experience before buprenorphine. They reported that while the oxycodone removed their pain, there was no sense of euphoria from the oxycodone. Tolerance/dose escalation has always been the major barrier to long-term opioid analgesia. The partial agonist buprenorphine appeared to anchor tolerance to the '40 mg methadone' level known to be the comparative potency of buprenorphine, allowing for long- term analgesic effects from mu opioid agonists.
  • 44. Preliminary investigations suggests that other potent mu agonists would be appropriate candidates for combination analgesia. For example, a dual patch method with fentanyl and buprenorphine. The effects of buprenorphine in mitigating euphoria suggest a role in affecting the current epidemic of opioid dependence. In other words, imagine if every opioid agonist was intrinsically attached to buprenorphine! Opioid dependence is currently at epidemic levels, and any means to reduce diversion of opioids will save lives. Combining buprenorphine or other partial agonists with agonists may be one answer to the opioid dependence problem. Such combinations may also reduce the risk of addiction for individual patients who are exposed to potent opioids after surgery.
  • 45. Good evidence that true pain is present  Stable on buprenorphine for at minimum several months  Evidence for motivation to avoid old life-style, i.e. sick and tired.  Trustworthy, non-using partner to witness/control medications
  • 46. Opioid analgesia is limited by tolerance, addiction and respiratory depression. Buprenorphine, when combined with a mu agonist, causes a range of effects. Patients experience dose-related analgesia from the agonist without euphoria. Patients unable to control their use of a mu agonist alone gain that control when on buprenorphine. And buprenorphine appears to anchor tolerance, maintaining analgesia without dose escalation. This finding offers huge implications for pain management.  Jeffrey T Junig MD PhD Fond du Lac Psychiatry Asst. Clinical Professor of Psychiatry Medical College of Wisconsin

Editor's Notes

  1. Found interesting the number of wars fought over opioids THAN—such as the first opium war that resulted and the ceding of Honk Kong over the the British. But also, the wars now. History truly repeats itself. I read of needle-exchange programs in many forms—the stjames society sending out free samples of heroin, for example- or methods backed by the deepest medical minds, recommending treating addiction to morphine using heroin, or vice versa… or by inducing an alkaloid-based delerirum for weeks to rid the affliction. Over the course of history, one society after another taxed, banned, and eventually liberated the powers of opium—usually only to go back to where they once started. Most recently, I read about battles the world health organization, blaming ‘overzealous inderdiction efforts for untreated pain. The PROP doctors are at war with the UW Public Health group. Some people are continuing to demand another pound of flesh from purduepharma.
  2. Found interesting the number of wars fought over opioids THAN—such as the first opium war that resulted and the ceding of Honk Kong over the the British. But also, the wars now. History truly repeats itself. I read of needle-exchange programs in many forms—the stjames society sending out free samples of heroin, for example- or methods backed by the deepest medical minds, recommending treating addiction to morphine using heroin, or vice versa… or by inducing an alkaloid-based delerirum for weeks to rid the affliction. Over the course of history, one society after another taxed, banned, and eventually liberated the powers of opium—usually only to go back to where they once started. Most recently, I read about battles the world health organization, blaming ‘overzealous inderdiction efforts for untreated pain. The PROP doctors are at war with the UW Public Health group. Some people are continuing to demand another pound of flesh from purduepharma.
  3. d