This pilot study examined 5 patients with severe, chronic pain conditions, and was presented at the 2012 ASAM Annual Meeting in Atlanta. Patients taking 4 mg of buprenorphine daily SL used oxycodone 15 mg, up to every 4 hours as needed in an open-label trial. Patients reported excellent analgesia with NO euphoria, such that even former opioid addicts were able to control use of their agonist each month. Most importantly, buprenorphine anchored tolerance and prevented dose escalation in patients for as long as 5 years, with no sign of tolerance development. Patients continued to get excellent paiin relief for many years, provided buprenorphine was not discontinued.

2. ASAM Disclosure of
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Content of Activity:
ASAM Medical –Scientific Conference 2012
Name Commercial Relevant Relevant No Relevant
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What Was For What Role with Any
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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.

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.

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.

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