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Uncoupling Mu-Receptor Analgesia,
Tolerance, and Euphoria
Modification of agonist effects using
buprenorphine
Jeffrey T Junig MD PhD
Fond du Lac Psychiatry
Asst. Clinical Professor of Psychiatry
Medical College of Wisconsin
ASAM Disclosure of Relevant Financial Relationships
Content of Activity: ASAM Medical –Scientific
Conference 2012
Name Commercial Interests
Relevant Financial
Relationships: What Was Received
Relevant Financial
Relationships: For What Role
No Relevant Financial
Relationships with Any
Commercial Interests
Forest Labs Speaker Bureau $2000 Speaking fees
Opium: A History. by Martin Booth 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.
400 AD
1200 AD Opium treats diarrhea
1600 Portuguese smoke opium1780 Persians drink opium
1803 Friedrich Sertürner invents morphine
1903 heroin use rises dramatically; US passes Pure Food and Drug Act requiring labels on patent medications; heroin availability decreases
1874 Heroin first synthesized by C. R. Wright
1972 Snyder and
Pert discover
opiate receptor
1975 Kosterlitz and
colleagues isolate an
endogenous opioid in the
brain, enkephalin2003 crackdown on online pharmacies
February 2009 FDA announces
plans further to restrict access to
opioid-based pain-relievers
March 2009 World Health
Organization: 80% of the world’s
population lacks access to pain
relief. Human Rights Watch
blames “over-zealous drug control
efforts”.
3400 BC-1300 BC opium spreads from Mesopotamia through Greece and Europe
1200 AD Opium treats diarrhea
1874 Heroin first synthesized by C. R. Wright
1972 Snyder and Pert discover opiate
receptor
DATA 2000
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.
Who Am I?
Jeffrey T Junig MD PhD
PhD Neurochemistry, University of Rochester Center for Brain
Research
MD U of R School of Medicine and Dentistry
Residency in Anesthesiology at Penn, Board Certified Anesthesiologist
Worked in pain clinics for 10 years
Personal opioid dependence– 2001 – treated ‘old fashioned way’
Residency in Psychiatry– Board Certified Psychiatrist
Solo practice; Asst Clinical Professor of Psychiatry, Medical College of
WI
There is no doubt that opioids have been one of the
most important forces behind the advance of
modern medicine.
J Junig, ASAM Annual Meeting 2012
Modern opioids have allowed for the creation of
modern surgical technique, eased suffering, allowed
death with dignity, and relieved pain in countless
situations, big and small.
And yet------
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.
Can some of the risks of opioids be separated from their benefits?
Buprenorphine for Opioid Dependence
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.
Findings- Acute Pain
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.
Question: Effects on Chronic Pain?
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.
But:
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
Analgesia in presence of buprenorphine has unique properties
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.
Technique
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.
Results
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.
Stopping buprenorphine?
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.
Findings
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.
Findings (cont)
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
Ideal Cases:
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
Summary